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Brambilla E, Brambilla DJF, Tregnago AC, Riva F, Pasqualotto FF, Soldera J. Exploring macrophage polarization as a prognostic indicator for colorectal cancer: Unveiling the impact of metalloproteinase mutations. World J Clin Cases 2025; 13:105011. [DOI: 10.12998/wjcc.v13.i23.105011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Revised: 03/24/2025] [Accepted: 05/07/2025] [Indexed: 06/04/2025] Open
Abstract
BACKGROUND Macrophages play a crucial role in the tumor microenvironment, displaying remarkable plasticity that allows them to either suppress or promote tumor progression. Their polarization into M1 or M2 phenotypes could have significant prognostic implications, and manipulating this polarization may offer a novel approach to controlling colorectal neoplasms.
AIM To evaluate the infiltration rates of M1 and M2 macrophages in colorectal neoplasia, specifically comparing cases with and without metalloproteinase mutations. Additionally, it sought to explore potential prognostic factors associated with the disease.
METHODS The study involved two cohorts of patients diagnosed with colorectal neoplasia: 33 patients with metalloproteinase mutations and 33 without. Macrophage quantity and polarization were assessed using markers indicative of M1 (iNOS) and M2 (CD163, CD206) macrophages. Prognostic factors and survival outcomes related to colorectal cancer (CRC) were also analyzed.
RESULTS Among the 61 patients, 28 (45.9%) exhibited metalloproteinase mutations, while 33 (54.1%) did not. Tumor staging revealed that 16.9% were in stage I, 34.2% in stage II, 42.4% in stage III, and 8.5% in stage IV. The study recorded 12 patient deaths (19.7%), with 21.2% from the control group and 17.9% from the mutation group. M2 macrophages, identified by CD163 and CD206 markers, had mean counts of 23 and 17, respectively, with standard deviations of 21 and 17. In contrast, M1 macrophages, identified by iNOS, had a mean count of five per site, with a standard deviation of 11.
CONCLUSION The study found no statistically significant differences in macrophage density between groups, irrespective of metalloproteinase mutation status, age, gender, tumor region, staging, TILS, tumor recurrence, or clinical outcomes. No association was observed between macrophage polarization and CRC prognosis or survival. However, patients with metalloproteinase mutations demonstrated a better survival rate, suggesting a potential protective role of this mutation in colorectal neoplasia.
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Affiliation(s)
- Eduardo Brambilla
- Clinical Gastroenterology, Universidade de Caxias do Sul, Caxias do Sul 95070-560, Rio Grande do Sul, Brazil
| | | | - Aline Caldart Tregnago
- Department of Pathology, Universidade de Caxias do Sul, Caxias do Sul 95070-560, Rio Grande do Sul, Brazil
| | - Floriano Riva
- Department of Pathology, Universidade de Caxias do Sul, Caxias do Sul 95070-560, Rio Grande do Sul, Brazil
| | - Fabio Firmbach Pasqualotto
- Department of Urology, Universidade de Caxias do Sul, Caxias do Sul 95070-560, Rio Grande do Sul, Brazil
| | - Jonathan Soldera
- Department of Gastroenterology and Acute Medicine, University of South Wales, Cardiff CF37 1DL, United Kingdom
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Cheng G, Yuan S, Wang J, Deng S, Wu Y, Wang Y, Shen Y, Li L. A prognostic nomogram for patients with III-IV nasopharyngeal carcinoma based on dynamic changes in the inflammatory and nutrition index. Clin Transl Oncol 2025; 27:2638-2650. [PMID: 39531145 DOI: 10.1007/s12094-024-03781-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2024] [Accepted: 10/30/2024] [Indexed: 11/16/2024]
Abstract
BACKGROUND The purpose of the study was to explore the value of dynamic changes in inflammatory and nutritional index after comprehensive treatment in patients with stage III-IVA nasopharyngeal carcinoma (NPC). A prognostic model was also established and validated for progression-free survival (PFS) of patients. METHODS We retrospectively selected 279 NPC patients with stage III-IVA. Their general clinical data and hematological index were collected and then calculated the changes during treatment. X-tile software was used to determine the optimal cut-off value. COX regression, Lasso method, and Boruta method were used to variable selection and model establishment. Using the bootstrap internal validation method, concordance index (C-index), calibration plot, and Kaplan-Meier curves were used to evaluate the model. To test the prognostic value of the model, we have also evaluated the performance of the nomogram against a conventional tumor metastasis staging system (TNM). RESULTS Multivariable COX regression analysis demonstrated that clinical staging, delta lymphocyte, delta monocyte, delta albumin, delta platelet-to-lymphocyte ratio and delta systemic immune inflammation index were related to the PFS of NPC patients. The C-index of the model was 0.712, and the calibration curve indicated that the model had good consistency. The C-index of the TNM staging system was 0.597, which was considerably lower compared to our model (P = 0.015). CONCLUSION We demonstrated the predictive value of dynamic changes in inflammatory and nutritional indices for the prognosis of NPC by successfully establishing and validating a prognostic model for predicting 1- and 3-year PFS after comprehensive treatment in patients with stage III-IVA NPC.
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Affiliation(s)
- Guangyi Cheng
- The First School of Clinical Medicine, Xuzhou Medical University, 9 Kunpeng Road, Xuzhou, Jiangsu, People's Republic of China
- Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Shiwang Yuan
- Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
| | - Jiang Wang
- The First School of Clinical Medicine, Xuzhou Medical University, 9 Kunpeng Road, Xuzhou, Jiangsu, People's Republic of China
- Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Sijia Deng
- The First School of Clinical Medicine, Xuzhou Medical University, 9 Kunpeng Road, Xuzhou, Jiangsu, People's Republic of China
- Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Yang Wu
- Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Yuyan Wang
- The First School of Clinical Medicine, Xuzhou Medical University, 9 Kunpeng Road, Xuzhou, Jiangsu, People's Republic of China
- Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Yu Shen
- The First School of Clinical Medicine, Xuzhou Medical University, 9 Kunpeng Road, Xuzhou, Jiangsu, People's Republic of China
- Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Liantao Li
- The First School of Clinical Medicine, Xuzhou Medical University, 9 Kunpeng Road, Xuzhou, Jiangsu, People's Republic of China.
- Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.
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Yan C, Wang G. Advances in research on flavonoids in tumor immunotherapy (Review). Mol Med Rep 2025; 31:150. [PMID: 40211703 PMCID: PMC11995692 DOI: 10.3892/mmr.2025.13515] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Accepted: 02/25/2025] [Indexed: 04/16/2025] Open
Abstract
Cancer immunotherapy is an approach used in anti‑tumor treatment; however, its efficacy is limited to specific tumor types that are inherently sensitive to immune system modulation. Expanding the scope of indications and enhancing the efficacy of cancer immunotherapy are key goals for continued advancement. Flavonoids modulate the tumor‑immunosuppressive microenvironment. Integrating flavonoids with immunotherapeutic modalities, including cancer vaccines, immune checkpoint inhibitors and adoptive immune‑cell therapy, has potential in terms of augmenting the therapeutic efficacy of immunotherapy. The present review aimed to summarize flavonoids that enhance cancer immunotherapy, focusing on their underlying mechanisms and the application of nanotechnology to overcome inherent limitations such as poor solubility, low bioavailability, rapid metabolism, and instability under physiological conditions, thereby highlighting the potential of flavonoids in advancing cancer immunotherapy.
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Affiliation(s)
- Chaoguang Yan
- Department of Oncology, Weifang Chinese Medicine Hospital, Weifang, Shandong 261000 P.R. China
| | - Guangchun Wang
- Department of Oncology, Weifang Chinese Medicine Hospital, Weifang, Shandong 261000 P.R. China
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Mo PL, Lin M, Gao BW, Zhang SB, Chen JP. Knowledge structure analysis and network visualization of tumor-associated macrophages in hepatocellular carcinoma research: A bibliometric mapping. World J Clin Oncol 2025; 16:102747. [DOI: 10.5306/wjco.v16.i5.102747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2024] [Revised: 02/13/2025] [Accepted: 04/11/2025] [Indexed: 05/19/2025] Open
Abstract
BACKGROUND Tumor-associated macrophages (TAMs) have demonstrated significant potential as a research and treatment approach for hepatocellular carcinoma (HCC). Nevertheless, a comprehensive quantitative analysis of TAMs in HCC remained insufficient. Therefore, the objective of this study was to employ bibliometric methods to investigate the development trends and research frontiers pertaining to this field.
AIM To determine the knowledge structure and current research hotspots by bibliometric analysis of scholarly papers pertaining to TAMs in HCC.
METHODS The present study employed the Web of Science Core Collection to identify all papers related to TAMs in HCC research. Utilizing the Analysis Platform of Bibliometrics, CiteSpace 6.2.R4, and Vosviewer 1.6.19, the study conducted a comprehensive analysis encompassing multiple dimensions such as publication quantity, countries of origin, affiliated institutions, publishing journals, contributing authors, co-references, author keywords, and emerging frontiers within this research domain.
RESULTS A thorough examination was undertaken on 818 papers within this particular field, published between January 1, 1985 to September 1, 2023, which has witnessed a substantial surge in scholarly contributions since 2012, with a notable outbreak in 2019. China was serving as the central hub in this field, with Fudan University leading in terms of publications and citations. Chinese scholars have taken the forefront in driving the research expansion within this field. Hepatology emerged as the most influential journal in this field. The study by Qian and Pollard in 2010 received the highest number of co-citations. It was observed that the citation bursts of references coincided with the outbreak of publications. Notably, “tumor microenvironment”, “immunotherapy”, “prognostic”, “inflammation”, and “polarization”, etc. emerged as frequently occurring keywords in this field. Of particular interest, “immune evasion”, “immune infiltration”, and “cancer genome atlas” were identified as emerging frontiers in recent research.
CONCLUSION The field of TAMs in HCC exhibited considerable potential, as evidenced by the promising prospects of immunotherapeutic interventions targeting TAMs for the amelioration of HCC. The emerging frontiers in this field primarily revolved around modulating the immunosuppressive characteristics of TAMs within a liver-specific immune environment, with a focus on how to counter immune evasion and reduce immune infiltration.
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Affiliation(s)
- Ping-Li Mo
- Shenzhen Key Laboratory of Hospital Chinese Medicine Preparation, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen 518033, Guangdong Province, China
| | - Ming Lin
- Department of Hepatology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510120, Guangdong Province, China
| | - Bo-Wen Gao
- Department of Traditional Chinese Medicine, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen 518107, Guangdong Province, China
| | - Shang-Bin Zhang
- Shenzhen Key Laboratory of Hospital Chinese Medicine Preparation, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen 518033, Guangdong Province, China
| | - Jian-Ping Chen
- Shenzhen Key Laboratory of Hospital Chinese Medicine Preparation, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen 518033, Guangdong Province, China
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Meng C, Lin K, Shi W, Teng H, Wan X, DeBruine A, Wang Y, Liang X, Leo J, Chen F, Gu Q, Zhang J, Van V, Maldonado KL, Gan B, Ma L, Lu Y, Zhao D. Histone methyltransferase ASH1L primes metastases and metabolic reprogramming of macrophages in the bone niche. Nat Commun 2025; 16:4681. [PMID: 40394007 PMCID: PMC12092585 DOI: 10.1038/s41467-025-59381-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Accepted: 04/22/2025] [Indexed: 05/22/2025] Open
Abstract
Bone metastasis is a major cause of cancer death; however, the epigenetic determinants driving this process remain elusive. Here, we report that histone methyltransferase ASH1L is genetically amplified and is required for bone metastasis in men with prostate cancer. ASH1L rewires histone methylations and cooperates with HIF-1α to induce pro-metastatic transcriptome in invading cancer cells, resulting in monocyte differentiation into lipid-associated macrophage (LA-TAM) and enhancing their pro-tumoral phenotype in the metastatic bone niche. We identified IGF-2 as a direct target of ASH1L/HIF-1α and mediates LA-TAMs' differentiation and phenotypic changes by reprogramming oxidative phosphorylation. Pharmacologic inhibition of the ASH1L-HIF-1α-macrophages axis elicits robust anti-metastasis responses in preclinical models. Our study demonstrates epigenetic alterations in cancer cells reprogram metabolism and features of myeloid components, facilitating metastatic outgrowth. It establishes ASH1L as an epigenetic driver priming metastasis and macrophage plasticity in the bone niche, providing a bona fide therapeutic target in metastatic malignancies.
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Affiliation(s)
- Chenling Meng
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Kevin Lin
- Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Wei Shi
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Hongqi Teng
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Xinhai Wan
- Department of Endocrine Neoplasia & Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Anna DeBruine
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
- The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, 77030, USA
| | - Yin Wang
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Xin Liang
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Javier Leo
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
- The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, 77030, USA
| | - Feiyu Chen
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Qianlin Gu
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Jie Zhang
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Vivien Van
- Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Kiersten L Maldonado
- Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Boyi Gan
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Li Ma
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Yue Lu
- Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
| | - Di Zhao
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
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Teng G, Zhang M, Pan Y, Karampoor S, Mirzaei R. Modulating the tumor microenvironment: The role of traditional Chinese medicine in improving lung cancer treatment. Open Life Sci 2025; 20:20251100. [PMID: 40417000 PMCID: PMC12103189 DOI: 10.1515/biol-2025-1100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Revised: 02/02/2025] [Accepted: 03/17/2025] [Indexed: 05/27/2025] Open
Abstract
The holistic approach of traditional Chinese medicine (TCM) has been increasingly being focused on as a potential adjuvant to conventional lung cancer therapies in an attempt at modulating the tumor microenvironment (TME). Covering a diverse range of herbal medicine, acupuncture, and dietary therapy, TCM brings a unique perspective to influencing the TME. Importantly, the study has found the effects of specific TCM compounds, such as cantharidin, boehmenan, shikonin, and salidroside, on lung cancer in the TME. These compounds interact intricately with key apoptotic regulators, oxidative stress pathways, and inflammation-related mechanisms, suggesting their potential role in enhancing conventional therapies. TCM compounds could modulate a variety of cellular and molecular pathways, potentially inhibiting tumor proliferation, invasion, and metastasis. Besides, the practices of TCM alleviate the side effects of conventional treatments and enhance immune function, hence promoting the quality of life among lung cancer patients. In this regard, this review gives a contemporary account of the state of affairs on the part of TCM within the framework of the treatment of lung cancer with reference to its recent developments, and diverse roles.
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Affiliation(s)
- Geling Teng
- Department of Respiratory and Critical Care Medicine, Shandong Public Health Clinical Center, Shandong University, Jinan, 250013, China
| | - Min Zhang
- Department of Respiratory and Critical Care Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China
| | - Yuling Pan
- School of Medicine, Shandong University of Traditional Chinese Medicine, Jinan, 250355, China
| | - Sajad Karampoor
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran
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Metwally S, Śmiałek-Bartyzel J, Pabijan J, Lekka M. Structural and Mechanical Characterization of Collagen-Hyaluronan Hydrogels Used to Study Cancer Cell Invasion through the Bladder Wall. ACS Biomater Sci Eng 2025. [PMID: 40373231 DOI: 10.1021/acsbiomaterials.5c00136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/17/2025]
Abstract
Collagen-hyaluronic acid (Col-HA) hydrogels are widely studied as biomimetic materials that recapitulate the environmental physical and mechanical properties crucial for understanding the cell behavior during cancer invasion and progression. Our research focused on Col-HA hydrogels as an environment to study the invasion of bladder cancer cells through the bladder wall. The bladder is a heterogeneous structure composed of three main layers: urothelium (the softest), lamina propria (the stiffest), and the muscle outer layer, with elastic properties lying between the two. Thus, the bladder cancer cells migrate through the mechanically distinct environments. We investigated the impact of Col-HA hydrogel microstructure and rheology on migrating bladder cancer T24 cells from the cancer spheroid surface to the surrounding environment formed from various collagen I and HA concentrations and chemical structures. The designed hydrogels showed variability in network density and rheological properties. The migration of bladder cancer cells was inhibited inside hydrogels of ∼1 kPa storage modulus. The correlation analysis showed that collagen concentration primarily defined the rheological properties of Col-HA hydrogels, but hydrogels can soften or stiffen depending on the type of HA used. Within soft Col-HA hydrogels, cells freely invade the surrounding environment, while its stiffening impedes cell movement and almost inhibits cell migration. Only individual, probably leading, cells are observed at the spheroid edges initiating the invasion. Our findings showed that the rheological properties of the hydrogels dominate in regulating cancer cell migration, providing a platform to study how bladder cancer cells migrate through the heterogeneous structure of the bladder wall.
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Affiliation(s)
- Sara Metwally
- Institute of Nuclear Physics, Polish Academy of Sciences, Krakow PL-31342, Poland
| | | | - Joanna Pabijan
- Institute of Nuclear Physics, Polish Academy of Sciences, Krakow PL-31342, Poland
| | - Małgorzata Lekka
- Institute of Nuclear Physics, Polish Academy of Sciences, Krakow PL-31342, Poland
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Ziadeh H, Calaway A, Gupta S, Bodner D, Brown JR, Schumacher FR, Wu CHW. Increased risk of upper tract urothelial carcinoma in patients with kidney stones: a large-scale analysis of the UK biobank. Urolithiasis 2025; 53:87. [PMID: 40335677 DOI: 10.1007/s00240-025-01758-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2025] [Accepted: 04/22/2025] [Indexed: 05/09/2025]
Abstract
Kidney stone disease is a common and increasingly prevalent condition, with its incidence rising by 70% over the past two decades in the U.S. Lodgment of stones within the ureteral wall can cause urothelial injury, triggering inflammation, edema, and obstruction. Chronic inflammation has been linked to cancer development, contributing to tumorigenesis through cellular transformation, proliferation, invasion, angiogenesis, and metastasis. Studies suggest that recurrent nephrolithiasis can lead to a range of complications, including an increased risk of urinary tract cancer. This study investigates the association between kidney and ureteral stones and upper tract urothelial carcinoma (UTUC) risk using data from 502,144 individuals in the UK Biobank. We bidirectionally examined the presence of kidney stones and UTUC, applying a chi-square test to compute the odds ratio and assess statistical significance. A history of kidney stones was noted in 13,016 individuals, while 489,128 were stone-free. Among 511 UTUC cases, 50 had a history of kidney stones, whereas 461 were isolated UTUC. In contrast, 12,966 individuals had kidney stones without UTUC, and 488,667 were free of both conditions. Statistical analysis revealed an increased risk of UTUC in individuals with kidney stones [OR = 4.09 (95% CI 3.05-5.48), p < 0.001], indicating strong statistical significance. Our study demonstrates a fourfold increased risk of UTUC in individuals with a history of kidney stones. These findings highlight a significant association between kidney stones and UTUC, underscoring the need for further research on clinical management and cancer surveillance.
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Affiliation(s)
- Hachem Ziadeh
- Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine and University Hospitals, Cleveland, OH, USA
- Department of Urology, Case Western Reserve University School of Medicine and University Hospitals, Cleveland, OH, USA
| | - Adam Calaway
- Department of Urology, Case Western Reserve University School of Medicine and University Hospitals, Cleveland, OH, USA
- Case Western Reserve School of Medicine, Cleveland, OH, USA
| | - Sanjay Gupta
- Department of Urology, Case Western Reserve University School of Medicine and University Hospitals, Cleveland, OH, USA
- Case Western Reserve School of Medicine, Cleveland, OH, USA
| | - Donald Bodner
- Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine and University Hospitals, Cleveland, OH, USA
- Department of Urology, Case Western Reserve University School of Medicine and University Hospitals, Cleveland, OH, USA
| | - Jason R Brown
- Department of Medical Oncology, University Hospitals, Seidman Cancer Center, Cleveland, OH, USA
| | - Fredrick R Schumacher
- Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - Chen-Han Wilfred Wu
- Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine and University Hospitals, Cleveland, OH, USA.
- Department of Urology, Case Western Reserve University School of Medicine and University Hospitals, Cleveland, OH, USA.
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Wu PY, Tsai YT, Lin YT, Chuang HC, Yang CH, Chien CY, Fang FM, Huang TL, Lu H, Tsai MH. Assessment of Preoperative Systemic Inflammation Response Index in Surgically Treated Young Head and Neck Cancer Patients Under 40. EAR, NOSE & THROAT JOURNAL 2025:1455613251338940. [PMID: 40327049 DOI: 10.1177/01455613251338940] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/07/2025] Open
Abstract
OBJECTIVES To assess the prognosis of young patients (≤40 years old) with head and neck squamous cell carcinoma (HNSCC), focusing on the preoperative Systemic Inflammation Response Index (SIRI). METHODS Between January 2007 and February 2017, 175 young patients with HNSCC (≤40 years old) who underwent radical surgery were retrospectively enrolled in this study. The patients were randomly divided into a training cohort (N = 131) and a validation cohort (N = 44). The SIRI is defined as the absolute neutrophil count (×10⁹/L) multiplied by the absolute monocyte count (×10⁹/L), divided by the absolute lymphocyte count (×10⁹/L) in peripheral blood, all measured within one week prior to radical surgery. Univariate and multivariate Cox regression analyses were conducted to identify variables associated with survival outcomes, which were then used to construct and evaluate a predictive nomogram. RESULTS In both the training and validation cohorts, patients were classified into low- and high-SIRI groups based on a cutoff value of 0.87, which was determined by receiver operating characteristic analysis. This SIRI cutoff effectively stratified patients into two distinct prognostic groups with significant survival differences. Multivariable Cox analysis identified the presence of lymphovascular invasion and the high preoperative SIRI as significant independent prognostic factors associated with poorer cancer-specific survival (CSS) in young patients with HNSCC. Using these variables, a predictive model for 5 year CSS was constructed and visualized as a nomogram. The model demonstrated strong predictive performance, with a C-index of 0.744 [95% CI (0.643-0.845)] in the training cohort and 0.839 [95% CI (0.740-0.938)] in the validation cohort. CONCLUSION Data from preoperative SIRI assessment, coupled with the presence of pathological adverse features, serve as valuable references for risk stratification in young patients with HNSCC.
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Affiliation(s)
- Pei-Yin Wu
- Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taiwan
| | - Yao-Te Tsai
- Department of Otolaryngology, Chiayi Chang Gung Memorial Hospital, Puzi, Taiwan
- School of Medicine, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Yu-Tsai Lin
- Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taiwan
- School of Medicine, Chang Gung University College of Medicine, Taoyuan, Taiwan
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- School of Medicine, College of Medicine, National Sun Yat-sen University, Kaohsiung, Taiwan
| | - Hui-Ching Chuang
- Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taiwan
- School of Medicine, Chang Gung University College of Medicine, Taoyuan, Taiwan
- School of Medicine, College of Medicine, National Sun Yat-sen University, Kaohsiung, Taiwan
| | - Chao-Hui Yang
- Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taiwan
- School of Medicine, Chang Gung University College of Medicine, Taoyuan, Taiwan
- School of Medicine, College of Medicine, National Sun Yat-sen University, Kaohsiung, Taiwan
| | - Chih-Yen Chien
- Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taiwan
- Doctoral Program of Clinical and Experimental Medicine, National Sun Yat-sen University, Kaohsiung, Taiwan
| | - Fu-Min Fang
- School of Medicine, Chang Gung University College of Medicine, Taoyuan, Taiwan
- School of Medicine, College of Medicine, National Sun Yat-sen University, Kaohsiung, Taiwan
- Department of Radiation Oncology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taiwan
| | - Tai-Lin Huang
- Department of Hematology and Oncology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taiwan
| | - Hui Lu
- Doctoral Program of Clinical and Experimental Medicine, National Sun Yat-sen University, Kaohsiung, Taiwan
| | - Ming-Hsien Tsai
- Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taiwan
- School of Medicine, Chang Gung University College of Medicine, Taoyuan, Taiwan
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- School of Medicine, College of Medicine, National Sun Yat-sen University, Kaohsiung, Taiwan
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Liu Z, Yang Y, Fang H, Cen B, Fan Y, Li J, Wang L, He S. Single-cell and spatial analyses reveal the effect of VSIG4 +S100A10 +TAMs on the immunosuppression of glioblastoma and anti-PD-1 immunotherapy. Int J Biol Macromol 2025; 308:142415. [PMID: 40127797 DOI: 10.1016/j.ijbiomac.2025.142415] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2024] [Revised: 03/04/2025] [Accepted: 03/21/2025] [Indexed: 03/26/2025]
Abstract
Therapeutic strategies aiming at the tumor immune microenvironment (TIME) hold promise for glioblastoma (GBM) treatment. However, adjuvant immunotherapies targeting checkpoint inhibitors just prove effective for a selected group of GBM patients. The extensive involvement of GBM-associated macrophages highlights their potential role in tumor behavior. In-depth exploration of the impact of macrophages on the efficacy of immunotherapy is crucial for enhancing treatment outcomes. In this study, we conducted a comprehensive analysis using bulk RNA-seq, single-cell RNA sequencing (scRNA-seq), and spatial transcriptomics to explore the heterogeneity of tumor-associated macrophages (TAMs) in GBM. Flow cytometry was employed to investigate the effects of VSIG4 on TAM phenotypes, and co-culture cellular assays were performed to evaluate its contribution to GBM malignancy. Integrating 16 patient samples, we examined the immunological significance of VSIG4+S100A10+TAMs. VSIG4 expression on macrophages is significantly upregulated and correlated with the TIME, promoting the polarization of macrophages towards M2 and facilitating GBM progression. Spatial transcriptomics and human samples multiplex immunofluorescence (mIF) confirmed the co-localization of VSIG4+S100A10+TAMs with various T cells, resulting in the inhibition of T cell immune responses and a reduction in anti-tumor immunity. Our findings demonstrate for the first time that VSIG4+S100A10+TAM is an independent prognostic indicator of poor outcome for GBM and markedly accumulates in patients exhibiting non-responsiveness to anti-PD-1 immunotherapy. Targeting this specific bifunctional subgroup can potentially open up new avenues for the immunotherapy of GBM.
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Affiliation(s)
- Ziyuan Liu
- Department of Pharmacy, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, Guangdong, China; National Medical Products Administration Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening & Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, Guangdong, China
| | - Yufan Yang
- National Medical Products Administration Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening & Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, Guangdong, China; Clinical Pharmacy Center, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China
| | - Haiting Fang
- Department of Pharmacy, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, Guangdong, China; National Medical Products Administration Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening & Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, Guangdong, China
| | - Bohong Cen
- National Medical Products Administration Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening & Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, Guangdong, China; Clinical Pharmacy Center, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China
| | - Yiqi Fan
- Department of Pharmacy, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, Guangdong, China; National Medical Products Administration Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening & Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, Guangdong, China
| | - Jianlong Li
- Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA; Department of Orthopedic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China.
| | - Lijie Wang
- Department of Pharmacy, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, Guangdong, China.
| | - Shuai He
- Department of Pharmacy, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, Guangdong, China; National Medical Products Administration Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening & Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, Guangdong, China.
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11
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Chen S, Wang Y, Dang J, Song N, Chen X, Wang J, Huang GN, Brown CE, Yu J, Weissman IL, Rosen ST, Feng M. CAR macrophages with built-In CD47 blocker combat tumor antigen heterogeneity and activate T cells via cross-presentation. Nat Commun 2025; 16:4069. [PMID: 40307254 PMCID: PMC12043996 DOI: 10.1038/s41467-025-59326-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2025] [Accepted: 04/15/2025] [Indexed: 05/02/2025] Open
Abstract
Macrophage-based cancer cellular therapy has gained substantial interest. However, the capability of engineered macrophages to target cancer heterogeneity and modulate adaptive immunity remains unclear. Here, exploiting the myeloid antibody-dependent cellular phagocytosis biology and phagocytosis checkpoint blockade, we report the enhanced synthetic phagocytosis receptor (eSPR) that integrate FcRγ-driven phagocytic chimeric antigen receptors (CAR) with built-in secreted CD47 blockers. The eSPR engineering empowers macrophages to combat tumor antigen heterogeneity. Transduced by adenoviral vectors, eSPR macrophages are intrinsically pro-inflammatory imprinted and resist tumoral polarization. Transcriptomically and phenotypically, eSPR macrophages elicit a more favorable tumor immune landscape. Mechanistically, eSPR macrophages in situ stimulate CD8 T cells via phagocytosis-dependent antigen cross-presentation. We also validate the functionality of the eSPR system in human primary macrophages.
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Affiliation(s)
- Siqi Chen
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA, USA
| | - Yingyu Wang
- City of Hope National Medical Center, Duarte, CA, USA
| | - Jessica Dang
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA, USA
| | - Nuozi Song
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA, USA
| | - Xiaoxin Chen
- Cardiovascular Research Institute & Department of Physiology, University of California, San Francisco, San Francisco, CA, USA
- Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA
| | - Jinhui Wang
- Integrative Genomics Core, Beckman Research Institute, City of Hope, Duarte, CA, USA
| | - Guo N Huang
- Cardiovascular Research Institute & Department of Physiology, University of California, San Francisco, San Francisco, CA, USA
- Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA
| | - Christine E Brown
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA, USA
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA
| | - Jianhua Yu
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA, USA
- City of Hope National Medical Center, Duarte, CA, USA
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA
- Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope, Duarte, CA, USA
| | - Irving L Weissman
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford Medicine, Stanford, CA, USA
- Department of Pathology, Stanford Medicine, Stanford, CA, USA
| | - Steven T Rosen
- City of Hope National Medical Center, Duarte, CA, USA
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA
- Beckman Research Institute, City of Hope, Duarte, CA, USA
| | - Mingye Feng
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA, USA.
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Nakatsukasa T, Muraoka D, Deng S, Yasui K, Sawada SI, Shimoda A, Matsushita H, Matsumoto K, Nagayasu T, Harada N, Akiyoshi K, Ikeda H. Antitumor immune response elicited by M2 TAM-specific DDS via C-type lectin CD209b using cholesteryl pullulan nanogel as a protein drug carrier. Biomater Sci 2025; 13:2340-2350. [PMID: 40094910 DOI: 10.1039/d5bm00342c] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/19/2025]
Abstract
Many cancer patients develop resistance to immunotherapy, highlighting the urgent need for novel therapeutic strategies. Various factors contribute to tumor resistance to immunotherapy, among which tumor-associated macrophages (TAMs) are critical regulators of tumor sensitivity. Therefore, combining cancer immunotherapies with drug delivery systems (DDSs) targeting TAMs has become an intriguing treatment strategy. However, the target molecules used in DDSs are limited to a few receptors expressed on TAMs. Therefore, the identification of novel target molecules for TAM-specific DDS is urgently needed. The current study evaluated the ability of a cholesteryl pullulan (CHP) nanogel to target TAMs via mDC-SIGN (CD209b). This nanogel encapsulated the cytotoxic protein drug Pseudomonas exotoxin A and was injected into a tumor-bearing mouse model. This treatment significantly reduced the abundance of CD209b-positive M2 TAMs and enhanced antitumor immune responses. Ultimately, tumor growth was suppressed, even in a low-immunogenic tumor model. Hence, CD209b is an effective target molecule for M2 TAM-specific DDSs that can be used to develop novel cancer therapies.
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Affiliation(s)
- Takaaki Nakatsukasa
- Department of Oncology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523, Japan.
- Department of Surgical Oncology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
| | - Daisuke Muraoka
- Department of Oncology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523, Japan.
- Division of Translational Oncoimmunology, Aichi Cancer Center Research Institute, Nagoya 464-8681, Japan.
| | - Situo Deng
- Department of Oncology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523, Japan.
| | - Kiyoshi Yasui
- Department of Oncology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523, Japan.
| | - Shin-Ichi Sawada
- Synergy Institute for Futuristic Mucosal Vaccine Research and Development (cSIMVa), Chiba University, Chiba 260-8670, Japan
| | - Asako Shimoda
- Department of Immunology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan
- The Hakubi Center for Advanced Research, Kyoto University, Kyoto, Japan
| | - Hirokazu Matsushita
- Division of Translational Oncoimmunology, Aichi Cancer Center Research Institute, Nagoya 464-8681, Japan.
| | - Keitaro Matsumoto
- Department of Surgical Oncology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
| | - Takeshi Nagayasu
- Department of Surgical Oncology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
| | | | - Kazunari Akiyoshi
- Department of Immunology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan
| | - Hiroaki Ikeda
- Department of Oncology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523, Japan.
- Leading Medical Research Core Unit, Nagasaki University Graduate School of Biomedical Science, Nagasaki 852-8523, Japan
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13
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Fudalej M, Krupa K, Badowska-Kozakiewicz A, Deptała A. Inflammation, Immunosuppression, and Immunotherapy in Pancreatic Cancer-Where Are We Now? Cancers (Basel) 2025; 17:1484. [PMID: 40361411 PMCID: PMC12070857 DOI: 10.3390/cancers17091484] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2025] [Revised: 04/22/2025] [Accepted: 04/26/2025] [Indexed: 05/15/2025] Open
Abstract
Pancreatic cancer (PC) is one of the most commonly diagnosed and deadliest neoplasms in the modern world. Over the past few years, the incidence of PC has risen with only a slight improvement in overall survival. Moreover, the improvement in survival is primarily driven by diagnoses in the localized stage of the disease, rather than by new treatment methods. The inflammatory process is a key mediator of PC development, yet PC is also one of the most immune-resistant tumors. Patients rarely benefit from monotherapy with immune checkpoint inhibitors; nevertheless, the latest biological findings on the complexity of the pancreatic tumor microenvironment might be translated into designing new clinical studies that combine various approaches to overcome single-agent immunotherapy resistance. On the other hand, focusing on inflammation may lead to the development of new inflammation-based prognostic markers for patients. This review aims to describe the current state of knowledge regarding the complex relationships between systemic and local inflammation, immune response, immunosuppression, and therapeutic options in PC.
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Affiliation(s)
- Marta Fudalej
- Department of Oncological Propaedeutics, Medical University of Warsaw, 01-445 Warsaw, Poland; (M.F.); (A.B.-K.)
- Department of Oncology, National Medical Institute of the Ministry of the Interior and Administration, 02-507 Warsaw, Poland
| | - Kamila Krupa
- Students’ Scientific Organization of Cancer Cell Biology, Department of Oncological Propaedeutics, Medical University of Warsaw, 01-445 Warsaw, Poland;
| | - Anna Badowska-Kozakiewicz
- Department of Oncological Propaedeutics, Medical University of Warsaw, 01-445 Warsaw, Poland; (M.F.); (A.B.-K.)
| | - Andrzej Deptała
- Department of Oncological Propaedeutics, Medical University of Warsaw, 01-445 Warsaw, Poland; (M.F.); (A.B.-K.)
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14
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Gao S, Jiang P, Tian R. Neutrophil-and-monocyte-to-lymphocyte ratio is positively associated with elevated prostate-specific antigen levels and high-risk prostate cancer: evidence from the NHANES (2003-2008). Front Cell Dev Biol 2025; 13:1573932. [PMID: 40352665 PMCID: PMC12062112 DOI: 10.3389/fcell.2025.1573932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2025] [Accepted: 04/14/2025] [Indexed: 05/14/2025] Open
Abstract
Introduction Prostate cancer (PCa) is a prevalent malignancy in men globally. The total prostate-specific antigen (TPSA) test is essential for PCa screening. The neutrophil-and-monocyte-to-lymphocyte ratio (NMLR) has emerged as a potential biomarker for various diseases, but its relationship with PCa and TPSA is yet to be studied. This research aims to explore the connection between NMLR and TPSA levels, as well as high-risk prostate cancer (HRPCa), utilizing data from the National Health and Nutrition Examination Survey (NHANES) spanning 2003 to 2008. Methods The study included 4,248 U.S. adult males. NMLR was calculated as the ratio of the combined counts of peripheral neutrophils and monocytes to the counts of peripheral lymphocytes. Weighted multiple linear and logistic regression models were used to analyze the relationship between NMLR, TPSA levels, and HRPCa. Results A significant positive association was found between elevated NMLR levels and increased TPSA (β = 0.35, 95% CI: 0.21-0.49), as well as higher odds of HRPCa (OR = 2.04, 95% CI: 1.55-2.68). Smooth curve fitting results indicate that there is a nonlinear positive correlation between NMLR and TPSA, as well as between NMLR and HRCa. Conclusion This study reveals a significant relationship between NMLR, TPSA levels, and HRPCa odds among U.S. males, suggesting that NMLR could be a valuable biomarker for assessing PCa risk, underscoring inflammation's role in prostate health. Further research is encouraged to explore its applications in early detection, treatment efficacy evaluation and risk stratification.
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Affiliation(s)
- Shang Gao
- Department of Urology, General Hospital of Northern Theater Command, Shenyang, Liaoning, China
- Department of Graduate School, China Medical University, Shenyang, China
| | - Ping Jiang
- Department of Urology, General Hospital of Northern Theater Command, Shenyang, Liaoning, China
| | - Renli Tian
- Department of Urology, General Hospital of Northern Theater Command, Shenyang, Liaoning, China
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15
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Fang D, Zhou L, Zheng B. Research Progress on the Immunological Correlation Between Papillary Thyroid Carcinoma and Hashimoto's Thyroiditis. J Immunol Res 2025; 2025:7192808. [PMID: 40313970 PMCID: PMC12043394 DOI: 10.1155/jimr/7192808] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Accepted: 04/02/2025] [Indexed: 05/03/2025] Open
Abstract
In recent years, a growing body of evidence has suggested a correlation between Hashimoto's thyroiditis (HT) and the onset and progression of papillary thyroid carcinoma (PTC). However, the mechanism underlying the relationship between HT and PTC remains incompletely understood. This review discusses the literature on the correlation between PTC and HT and summarizes the research concerning the immunological interplay between these two conditions. It also delves into tumor-associated cells (such as CD8+ T cells), tumor-associated macrophages (TAMs), regulatory T cells (Tregs), and cancer-associated fibroblasts (CAFs), alongside other tumor-associated factors, including interleukins (ILs), interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and hypoxia-inducible factor-1 (HIF-1), highlighting their roles in the interaction between PTC and HT. We also explore the strategic direction of immunotherapy in thyroid malignancies, particularly PTC with HT, and propose novel targeted immunotherapies for advanced thyroid cancer.
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Affiliation(s)
- Digui Fang
- Department of Thyroid and Parathyroid Surgery, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China
| | - Limei Zhou
- Department of Thyroid and Parathyroid Surgery, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China
| | - Biao Zheng
- Department of Thyroid and Parathyroid Surgery, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China
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16
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Jones DC, Irving L, Dudley R, Blümli S, Wolny M, Chatzopoulou EI, Pryts S, Ahuja S, Rees DG, Sandercock AM, Rajan S, Varkey R, Kierny M, Kayserian A, Mulgrew K, Bowyer G, Songvilay S, Bienkowska K, Glover MS, Hess S, Dovedi SJ, Wilkinson RW, Arnaldez F, Cobbold M. LILRB2 blockade facilitates macrophage repolarization and enhances T cell-mediated antitumor immunity. J Immunother Cancer 2025; 13:e010012. [PMID: 40246582 PMCID: PMC12007065 DOI: 10.1136/jitc-2024-010012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Accepted: 03/16/2025] [Indexed: 04/19/2025] Open
Abstract
BACKGROUND Immune checkpoint inhibitors have revolutionized the treatment of solid tumors, enhancing clinical outcomes by releasing T cells from inhibitory effects of receptors like programmed cell death protein 1 (PD-1). Despite these advancements, achieving durable antitumor responses remains challenging, often due to additional immunosuppressive mechanisms within the tumor microenvironment (TME). Tumor-associated macrophages (TAMs) contribute significantly to the immunosuppressive TME and play a pivotal role in shaping T cell-mediated antitumor responses. Leukocyte immunoglobulin-like receptor subfamily B member 2 (LILRB2), expressed on myeloid cells, including TAMs, is an inhibitory receptor, which contributes to macrophage-mediated immunosuppression. In this study, we present AZD2796, a high-affinity anti-LILRB2 antibody designed to repolarize TAMs from an immunosuppressive to a proinflammatory phenotype. METHODS Anti-LILRB2 antibodies were identified using single-B-cell encapsulation Immune Replica technology. The ability of AZD2796 to enhance proinflammatory responses from macrophages treated with CD40 ligand or lipopolysaccharide was assessed using a macrophage stimulation assay. A tumor cell/macrophage/T cell co-culture assay was developed to evaluate the effect of AZD2796, as a single agent and in combination with an anti-PD-1 antibody, on the cytolytic activity of antigen-specific T cells. In vivo assessments were then carried out to determine the ability of AZD2796 to alter tumor growth rate in mice humanized with CD34 hematopoietic stem cells. RESULTS In preclinical assessments, AZD2796 skewed macrophage differentiation away from an immunosuppressive phenotype and enhanced the proinflammatory function of macrophages. AZD2796 significantly increased the anti-tumor response of T cells following PD-1 checkpoint blockade, while AZD2796 monotherapy reduced tumor growth in humanized mouse models. CONCLUSIONS These findings support the potential of AZD2796 as an anti-cancer therapy, with the ability to synergize with T-cell-based therapeutics.
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Affiliation(s)
- Des C Jones
- ICC, Early Oncology R&D, AstraZeneca, Cambridge, UK
- Immunocore Ltd, Abingdon, UK
| | | | | | | | - Marcin Wolny
- Biologics Engineering, AstraZeneca, Cambridge, UK
| | | | - Stacy Pryts
- ICC, Early Oncology R&D, AstraZeneca, Gaithersburg, Maryland, USA
| | - Shreya Ahuja
- Dynamic Omics, CGR, Discovery Sciences, R&D, AstraZeneca, Gaithersburg, Maryland, USA
| | | | | | - Saravanan Rajan
- Biologics Engineering, AstraZeneca, Gaithersburg, Maryland, USA
| | - Reena Varkey
- Biologics Engineering, AstraZeneca, Gaithersburg, Maryland, USA
| | - Michael Kierny
- Biologics Engineering, AstraZeneca, Gaithersburg, Maryland, USA
| | | | - Kathy Mulgrew
- ICC, Early Oncology R&D, AstraZeneca, Gaithersburg, Maryland, USA
| | | | | | | | - Matthew S Glover
- Dynamic Omics, CGR, Discovery Sciences, R&D, AstraZeneca, Gaithersburg, Maryland, USA
| | - Sonja Hess
- Dynamic Omics, CGR, Discovery Sciences, R&D, AstraZeneca, Gaithersburg, Maryland, USA
| | | | - Robert W Wilkinson
- ICC, Early Oncology R&D, AstraZeneca, Cambridge, UK
- Immunocore Ltd, Abingdon, UK
| | | | - Mark Cobbold
- ICC, Early Oncology R&D, AstraZeneca, Gaithersburg, Maryland, USA
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17
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D'Alterio C, Rea G, Napolitano M, Coppola E, Spina A, Russo D, Azzaro R, Mignogna C, Scognamiglio G, Califano D, Arenare L, Schettino C, Pisano C, Cecere SC, Di Napoli M, Passarelli A, Perrone F, Pignata S, Scala S. Association of peripheral monocytic myeloid-derived suppressor cells with molecular subtypes in single-center endometrial cancer patients receiving carboplatin + paclitaxel/avelumab (MITO-END3 trial). Cancer Immunol Immunother 2025; 74:172. [PMID: 40244420 PMCID: PMC12006586 DOI: 10.1007/s00262-025-04021-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2025] [Accepted: 03/14/2025] [Indexed: 04/18/2025]
Abstract
The MITO-END3 trial compared carboplatin and paclitaxel (CP) with avelumab plus carboplatin and paclitaxel (CPA) as first-line treatment in endometrial cancer (EC) patients and demonstrated a significant interaction between avelumab response and mismatch repair status. To investigate prognostic/predictive biomarker, 29 MITO-END3-EC patients were evaluated at pretreatment (B1) and at the end of CP/CPA treatment (B2) for peripheral myeloid-derived suppressor cells (MDSC) and Tregs. At B2, effector Tregs frequency was significantly higher in patients treated with CPA as compared to CP (p = 0.038). Both treatments (CP/CPA) induced significant decrease in peripheral M-MDSC (- 5.41%) in TCGA 2-MSI-high as compared to TCGA-category 4 tumors (p = 0.004). In accordance, both treatments induced M-MDSCs (+ 5.34%) in MSS patients as compared to MSI-high patients (p = 0.001). Moreover, in a subgroup of patients, primary tumors were highly infiltrated by M-MDSCs in MSS as compared to MSI-high ECs. A post hoc analysis displayed higher frequency of M-MDSCs (p = 0.020) and lower frequency of CD4+ (p < 0.005) at pretreatment in EC patients as compared to healthy donors. In conclusion, the peripheral evaluation of MDSCs and Tregs correlated with molecular features in EC treated with CP/CPA and may add insights in identifying EC patients responder to first-line chemo/chemo-immunotherapy.
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Affiliation(s)
- C D'Alterio
- Microenvironment Molecular Targets, Istituto Nazionale per lo Studio e la Cura dei Tumori-IRCCS-Fondazione "G. Pascale", Via M. Semmola, 80131, Naples, Italy
| | - G Rea
- Microenvironment Molecular Targets, Istituto Nazionale per lo Studio e la Cura dei Tumori-IRCCS-Fondazione "G. Pascale", Via M. Semmola, 80131, Naples, Italy
| | - M Napolitano
- Microenvironment Molecular Targets, Istituto Nazionale per lo Studio e la Cura dei Tumori-IRCCS-Fondazione "G. Pascale", Via M. Semmola, 80131, Naples, Italy
| | - E Coppola
- Uro-Gynecology Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori-IRCCS-Fondazione "G. Pascale", 80131, Naples, Italy
| | - A Spina
- Microenvironment Molecular Targets, Istituto Nazionale per lo Studio e la Cura dei Tumori-IRCCS-Fondazione "G. Pascale", Via M. Semmola, 80131, Naples, Italy
| | - D Russo
- Microenvironment Molecular Targets, Istituto Nazionale per lo Studio e la Cura dei Tumori-IRCCS-Fondazione "G. Pascale", Via M. Semmola, 80131, Naples, Italy
| | - R Azzaro
- Transfusion Medicine Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori-IRCCS-Fondazione "G. Pascale", 80131, Naples, Italy
| | - C Mignogna
- Pathology, Istituto Nazionale per lo Studio e la Cura dei Tumori-IRCCS-Fondazione "G. Pascale", 80131, Naples, Italy
| | - G Scognamiglio
- Pathology, Istituto Nazionale per lo Studio e la Cura dei Tumori-IRCCS-Fondazione "G. Pascale", 80131, Naples, Italy
| | - D Califano
- Microenvironment Molecular Targets, Istituto Nazionale per lo Studio e la Cura dei Tumori-IRCCS-Fondazione "G. Pascale", Via M. Semmola, 80131, Naples, Italy
| | - L Arenare
- Clinical Trial Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori-IRCCS-Fondazione "G. Pascale", 80131, Naples, Italy
| | - C Schettino
- Clinical Trial Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori-IRCCS-Fondazione "G. Pascale", 80131, Naples, Italy
| | - C Pisano
- Uro-Gynecology Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori-IRCCS-Fondazione "G. Pascale", 80131, Naples, Italy
| | - S C Cecere
- Uro-Gynecology Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori-IRCCS-Fondazione "G. Pascale", 80131, Naples, Italy
| | - M Di Napoli
- Uro-Gynecology Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori-IRCCS-Fondazione "G. Pascale", 80131, Naples, Italy
| | - A Passarelli
- Uro-Gynecology Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori-IRCCS-Fondazione "G. Pascale", 80131, Naples, Italy
| | - F Perrone
- Clinical Trial Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori-IRCCS-Fondazione "G. Pascale", 80131, Naples, Italy
| | - S Pignata
- Uro-Gynecology Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori-IRCCS-Fondazione "G. Pascale", 80131, Naples, Italy
| | - S Scala
- Microenvironment Molecular Targets, Istituto Nazionale per lo Studio e la Cura dei Tumori-IRCCS-Fondazione "G. Pascale", Via M. Semmola, 80131, Naples, Italy.
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Qi L, Zhou B, Chen J, Xu K, Wang K, Zheng S, Hu W, Yang Y. HOXC6 promotes the metastasis of MSI-H CRC by interacting with M2 macrophages and inducing effector T cell exhaustion. Cell Commun Signal 2025; 23:168. [PMID: 40186205 PMCID: PMC11971778 DOI: 10.1186/s12964-025-02167-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Accepted: 03/21/2025] [Indexed: 04/07/2025] Open
Abstract
We previously discovered that HOXC6 was the most significantly upregulated gene in right-sided colon cancer compared to left-sided colon cancer according to our previous study; however, the role of HOXC6 in microsatellite instability-high (MSI-H) tumors remains poorly understood. Here, multiple public datasets, and in-house cohorts were used to analyze the differential expression and prognostic role of HOXC6 in colorectal cancer (CRC). Immunohistochemistry and immunofluorescence were performed to evaluate the correlation between HOXC6 expression and M2 macrophage infiltration. CCK8 and Transwell assays were used to evaluate the proliferation and migration of tumor cells in vitro. BALB/c nude mice were utilized to construct a humanized immune system model to evaluate the efficacy of ruxolitinib in vivo. We found that HOXC6 was overexpressed in MSI-H CRC and associated with a poor prognosis. Upregulation of CCL2 by HOXC6 increased M2 macrophage infiltration. IL6 secreted by M2 macrophages induced the epithelial-mesenchymal transition of tumor cells by upregulating HOXC6. M2 macrophages promoted effector T cell exhaustion by downregulating 4-1BB. Thus, inhibition of the IL6/JAK pathway in M2 macrophages restored 4-1BB expression and T-cell cytotoxicity offering a promising therapeutic target for the treatment of HOXC6-overexpressing MSI-H CRC.
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Affiliation(s)
- Lina Qi
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, China
| | - Biting Zhou
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, China
| | - Jiani Chen
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, China
| | - Kailun Xu
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, China
| | - Kailai Wang
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, China
| | - Shu Zheng
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, China
| | - Wangxiong Hu
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, China.
- Research Center for Air Pollution and Health, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, China.
| | - Yanmei Yang
- Key Laboratory of Reproductive and Genetics, Ministry of Education, Women'S Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310006, China.
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Abouzeid HA, Kassem L, Liu X, Abuelhana A. Paclitaxel resistance in breast cancer: Current challenges and recent advanced therapeutic strategies. Cancer Treat Res Commun 2025; 43:100918. [PMID: 40215760 DOI: 10.1016/j.ctarc.2025.100918] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2025] [Revised: 03/14/2025] [Accepted: 03/30/2025] [Indexed: 05/04/2025]
Abstract
Breast cancer (BC) is one of the leading causes of cancer-related deaths among women worldwide. Paclitaxel (PTX), a chemotherapeutic agent derived from the taxane family, is commonly used in treating BC due to its ability to disrupt microtubule dynamics and induce cell death. However, resistance to PTX presents a significant challenge, as it diminishes the drug's effectiveness and can lead to treatment failure. This review explores the mechanisms by which PTX exerts its effects and the various factors contributing to resistance. These factors include genetic mutations that affect tubulin dynamics, the role of non-coding RNAs, molecular pathways involved in chemoresistance, epigenetic changes, post-transcriptional modifications, increased activity of ABC transporters that promote drug efflux, immunosuppressive interactions within the tumor microenvironment, and resistance mediated by autophagy. This review also explores strategies to overcome PTX resistance, including molecular and genetic innovations, combination therapies, and nanotechnology-based approaches. These strategies may improve PTX efficacy and enhance treatment outcomes for BC patients.
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Affiliation(s)
- Heidi A Abouzeid
- School of Pharmaceutical Sciences, Medical Research Institute, Southwest University, Chongqing 400716, China; Department of Clinical Pharmacy, Faculty of Pharmacy, New Valley University, Egypt.
| | - Loay Kassem
- Department of Clinical Oncology, Faculty of Medicine, Cairo University, Egypt
| | - Xuemei Liu
- School of Pharmaceutical Sciences, Medical Research Institute, Southwest University, Chongqing 400716, China
| | - Ahmed Abuelhana
- Department of Clinical Pharmacy and Pharmacy Practice, School of Pharmacy & Pharmaceutics Sciences, Ulster University, UK
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20
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Yang Z, Wang Y, Wang C, Li W, Wang F, He A, Han N, Ruan M. Preoperative platelet-to-lymphocyte ratio and lymphocyte-to-monocyte ratio predict poor prognosis in patients diagnosed with salivary gland adenoid cystic carcinoma. J Craniomaxillofac Surg 2025:S1010-5182(25)00028-9. [PMID: 40140268 DOI: 10.1016/j.jcms.2025.01.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Revised: 01/15/2025] [Accepted: 01/17/2025] [Indexed: 03/28/2025] Open
Abstract
BACKGROUND To assess the prognostic utility of preoperative neutrophil-to- lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) in the peripheral blood of patients diagnosed with salivary adenoid cystic carcinoma (SACC). METHODS Data from 310 patients diagnosed with SACC between January 2008 and April 2014 were included. Data were acquired from patient medical records and follow-ups. Receiver operating characteristic (ROC) curve analysis was used to determine the optimal cut-off values for NLR, PLR, and LMR. Kaplan-Meier and multivariate Cox regression analyses were used to evaluate the impact of NLR, PLR, and LMR on overall survival. RESULTS According to ROC curve analysis, the optimal cut-off values for NLR, PLR and LMR were 1.65, 105.13, and 3.38, respectively. A high PLR was significantly associated with cervical lymph node metastasis (P = 0.043), while low LMR was significantly associated with tumor size (P = 0.016). In addition, patients with PLR >105.13 (P < 0.001) and LMR <3.38 (P < 0.001) experienced worse overall survival rates according to univariate analysis. Multivariate Cox proportional hazards regression modeling demonstrated that histological grade, high PLR, and low LMR were independent prognostic factors for overall survival in patients with SACC. CONCLUSIONS Both pretreatment PLR and LMR were independent predictors of poor prognosis in patients with SACC, and may be considered accurate, low-cost, and readily obtainable clinical prognostic parameters.
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Affiliation(s)
- Zhibin Yang
- College & Hospital of Stomatology, Anhui Medical University, Key Lab. of Oral Diseases Research of Anhui Province, Hefei, 230032, China
| | - Yizhen Wang
- College & Hospital of Stomatology, Anhui Medical University, Key Lab. of Oral Diseases Research of Anhui Province, Hefei, 230032, China
| | - Chunyun Wang
- College & Hospital of Stomatology, Anhui Medical University, Key Lab. of Oral Diseases Research of Anhui Province, Hefei, 230032, China
| | - Wei Li
- College & Hospital of Stomatology, Anhui Medical University, Key Lab. of Oral Diseases Research of Anhui Province, Hefei, 230032, China
| | - Feiyu Wang
- College & Hospital of Stomatology, Anhui Medical University, Key Lab. of Oral Diseases Research of Anhui Province, Hefei, 230032, China
| | - Ading He
- Department of Dentistry, Affiliated Hospital, Weifang Medical University, Weifang, 261031, China
| | - Nannan Han
- Department of Oral Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China; Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, National Clinical Research Center for Oral Diseases, Shanghai, 200011, China.
| | - Min Ruan
- Department of Oral Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China; Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, National Clinical Research Center for Oral Diseases, Shanghai, 200011, China.
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21
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Jiang R, Yang L, Liu X, Xu Y, Han L, Chen Y, Gao G, Wang M, Su T, Li H, Fang L, Sun N, Du H, Zheng J, Wang G. Genetically engineered macrophages reverse the immunosuppressive tumor microenvironment and improve immunotherapeutic efficacy in TNBC. Mol Ther 2025:S1525-0016(25)00198-4. [PMID: 40119517 DOI: 10.1016/j.ymthe.2025.03.024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Revised: 01/21/2025] [Accepted: 03/17/2025] [Indexed: 03/24/2025] Open
Abstract
The main challenges in current immunotherapy for triple-negative breast cancer (TNBC) lie in the immunosuppressive tumor microenvironment (TME). Considering tumor-associated macrophages (TAMs) are the most abundant immune cells in the TME, resetting TAMs is a promising strategy for ameliorating the immunosuppressive TME. Here, we developed genetically engineered macrophages (GEMs) with gene-carrying adenoviruses, to maintain the M1-like phenotype and directly deliver the immune regulators interleukin-12 and CXCL9 into local tumors, thereby reversing the immunosuppressive TME. In tumor-bearing mice, GEMs demonstrated targeted enrichment in tumors and successfully reprogramed TAMs to M1-like macrophages. Moreover, GEMs significantly enhanced the accumulation, proliferation, and activation of CD8+ T cells, mature dendritic cells, and natural killer cells within tumors, while diminishing M2-like macrophages, immunosuppressive myeloid-derived suppressor cells, and regulatory T cells. This treatment efficiently suppressed tumor growth. In addition, combination therapy with GEMs and anti-programmed cell death protein 1 further improved interferon-γ+CD8+ T cell percentages and tumor inhibition efficacy in an orthotopic murine TNBC model. Therefore, this study provides a novel strategy for reversing the immunosuppressive TME and improving immunotherapeutic efficacy through live macrophage-mediated gene delivery.
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Affiliation(s)
- Ranran Jiang
- Department of Oncology, Nanjing Medical University, 101 Longmian Avenue, Nanjing, Jiangsu 211166, China; Cancer Institute, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu 221004, China; Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, 99 Huaihai Road, Xuzhou, Jiangsu 221002, China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu 221004, China; Department of Oncology, The Affiliated Hospital of Xuzhou Medical University, 99 Huaihai Road, Xuzhou, Jiangsu 221002, China
| | - Liechi Yang
- Department of Neurosurgery, The Affiliated Hospital of Xuzhou Medical University, 99 Huaihai Road, Xuzhou, Jiangsu 221002, China
| | - Xin Liu
- Cancer Institute, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu 221004, China; Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, 99 Huaihai Road, Xuzhou, Jiangsu 221002, China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu 221004, China; Department of Urology, The Affiliated Hospital of Xuzhou Medical University, 99 Huaihai Road, Xuzhou, Jiangsu 221002, China
| | - Yujun Xu
- Cancer Institute, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu 221004, China; Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, 99 Huaihai Road, Xuzhou, Jiangsu 221002, China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu 221004, China
| | - Lulu Han
- Cancer Institute, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu 221004, China; Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, 99 Huaihai Road, Xuzhou, Jiangsu 221002, China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu 221004, China
| | - Yuxin Chen
- Cancer Institute, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu 221004, China; Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, 99 Huaihai Road, Xuzhou, Jiangsu 221002, China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu 221004, China
| | - Ge Gao
- Cancer Institute, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu 221004, China; Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, 99 Huaihai Road, Xuzhou, Jiangsu 221002, China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu 221004, China
| | - Meng Wang
- Cancer Institute, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu 221004, China; Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, 99 Huaihai Road, Xuzhou, Jiangsu 221002, China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu 221004, China
| | - Tong Su
- Cancer Institute, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu 221004, China; Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, 99 Huaihai Road, Xuzhou, Jiangsu 221002, China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu 221004, China
| | - Huizhong Li
- Cancer Institute, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu 221004, China; Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, 99 Huaihai Road, Xuzhou, Jiangsu 221002, China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu 221004, China
| | - Lin Fang
- Cancer Institute, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu 221004, China; Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, 99 Huaihai Road, Xuzhou, Jiangsu 221002, China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu 221004, China
| | - Nan Sun
- Cancer Institute, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu 221004, China; Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, 99 Huaihai Road, Xuzhou, Jiangsu 221002, China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu 221004, China
| | - Hongwei Du
- Cancer Institute, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu 221004, China; Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, 99 Huaihai Road, Xuzhou, Jiangsu 221002, China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu 221004, China
| | - Junnian Zheng
- Department of Oncology, Nanjing Medical University, 101 Longmian Avenue, Nanjing, Jiangsu 211166, China; Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, 99 Huaihai Road, Xuzhou, Jiangsu 221002, China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu 221004, China.
| | - Gang Wang
- Cancer Institute, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu 221004, China; Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, 99 Huaihai Road, Xuzhou, Jiangsu 221002, China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu 221004, China.
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Turlej E, Domaradzka A, Radzka J, Drulis-Fajdasz D, Kulbacka J, Gizak A. Cross-Talk Between Cancer and Its Cellular Environment-A Role in Cancer Progression. Cells 2025; 14:403. [PMID: 40136652 PMCID: PMC11940884 DOI: 10.3390/cells14060403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2025] [Revised: 02/27/2025] [Accepted: 03/06/2025] [Indexed: 03/27/2025] Open
Abstract
The tumor microenvironment is a dynamic and complex three-dimensional network comprising the extracellular matrix and diverse non-cancerous cells, including fibroblasts, adipocytes, endothelial cells and various immune cells (lymphocytes T and B, NK cells, dendritic cells, monocytes/macrophages, myeloid-derived suppressor cells, and innate lymphoid cells). A constantly and rapidly growing number of studies highlight the critical role of these cells in shaping cancer survival, metastatic potential and therapy resistance. This review provides a synthesis of current knowledge on the modulating role of the cellular microenvironment in cancer progression and response to treatment.
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Affiliation(s)
- Eliza Turlej
- Departament of Molecular Physiology and Neurobiology, University of Wrocław, ul. Sienkiewicza 21, 50-335 Wrocław, Poland; (E.T.); (A.D.); (J.R.)
| | - Aleksandra Domaradzka
- Departament of Molecular Physiology and Neurobiology, University of Wrocław, ul. Sienkiewicza 21, 50-335 Wrocław, Poland; (E.T.); (A.D.); (J.R.)
| | - Justyna Radzka
- Departament of Molecular Physiology and Neurobiology, University of Wrocław, ul. Sienkiewicza 21, 50-335 Wrocław, Poland; (E.T.); (A.D.); (J.R.)
| | - Dominika Drulis-Fajdasz
- Departament of Molecular Physiology and Neurobiology, University of Wrocław, ul. Sienkiewicza 21, 50-335 Wrocław, Poland; (E.T.); (A.D.); (J.R.)
| | - Julita Kulbacka
- Departament of Molecular and Cellular Biology, Faculty of Pharmacy, Wrocław Medical University, Borowska 211A, 50-556 Wrocław, Poland;
- Department of Immunology and Bioelectrochemistry, State Research Institute Centre for Innovative Medicine, LT-08406 Vilnius, Lithuania
| | - Agnieszka Gizak
- Departament of Molecular Physiology and Neurobiology, University of Wrocław, ul. Sienkiewicza 21, 50-335 Wrocław, Poland; (E.T.); (A.D.); (J.R.)
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Guan F, Wang R, Yi Z, Luo P, Liu W, Xie Y, Liu Z, Xia Z, Zhang H, Cheng Q. Tissue macrophages: origin, heterogenity, biological functions, diseases and therapeutic targets. Signal Transduct Target Ther 2025; 10:93. [PMID: 40055311 PMCID: PMC11889221 DOI: 10.1038/s41392-025-02124-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2024] [Revised: 11/01/2024] [Accepted: 12/15/2024] [Indexed: 05/04/2025] Open
Abstract
Macrophages are immune cells belonging to the mononuclear phagocyte system. They play crucial roles in immune defense, surveillance, and homeostasis. This review systematically discusses the types of hematopoietic progenitors that give rise to macrophages, including primitive hematopoietic progenitors, erythro-myeloid progenitors, and hematopoietic stem cells. These progenitors have distinct genetic backgrounds and developmental processes. Accordingly, macrophages exhibit complex and diverse functions in the body, including phagocytosis and clearance of cellular debris, antigen presentation, and immune response, regulation of inflammation and cytokine production, tissue remodeling and repair, and multi-level regulatory signaling pathways/crosstalk involved in homeostasis and physiology. Besides, tumor-associated macrophages are a key component of the TME, exhibiting both anti-tumor and pro-tumor properties. Furthermore, the functional status of macrophages is closely linked to the development of various diseases, including cancer, autoimmune disorders, cardiovascular disease, neurodegenerative diseases, metabolic conditions, and trauma. Targeting macrophages has emerged as a promising therapeutic strategy in these contexts. Clinical trials of macrophage-based targeted drugs, macrophage-based immunotherapies, and nanoparticle-based therapy were comprehensively summarized. Potential challenges and future directions in targeting macrophages have also been discussed. Overall, our review highlights the significance of this versatile immune cell in human health and disease, which is expected to inform future research and clinical practice.
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Affiliation(s)
- Fan Guan
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Ruixuan Wang
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Zhenjie Yi
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Peng Luo
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Wanyao Liu
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Yao Xie
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Zaoqu Liu
- Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zhiwei Xia
- Department of Neurology, Hunan Aerospace Hospital, Hunan Normal University, Changsha, China.
| | - Hao Zhang
- Department of Neurosurgery, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
| | - Quan Cheng
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.
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Al-Omar A, Asadi M, Mert U, Muftuoglu C, Karakus HS, Goksel T, Caner A. Effects of Vinorelbine on M2 Macrophages in Non-Small Cell Lung Cancer. Int J Mol Sci 2025; 26:2252. [PMID: 40076874 PMCID: PMC11900078 DOI: 10.3390/ijms26052252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2025] [Revised: 02/25/2025] [Accepted: 03/01/2025] [Indexed: 03/14/2025] Open
Abstract
Tumor-associated macrophages (TAMs) significantly influence tumor progression and patient responses to conventional chemotherapy. However, the interplay between anti-cancer drugs, immune responses in the tumor microenvironment, and their implications for cancer treatment remains poorly understood. This study investigates the effects of vinorelbine on M2 macrophages in lung cancer and its capacity to modulate TAMs toward an M1 phenotype. Peripheral blood mononuclear cells (PBMCs) were polarized into M2 macrophages, and subsequent phenotype alterations upon vinorelbine treatment were assessed. Additionally, we evaluated vinorelbine's impact on gene and protein expression associated with cancer progression and cell invasion in non-small-cell lung cancer (NSCLC) cells indirectly co-cultured with M2 macrophages. Notably, vinorelbine, particularly at low concentrations, reprogrammed M2 macrophages to exhibit M1-like characteristics. While M2 macrophages enhanced cancer cell invasion, vinorelbine significantly mitigated this effect. M2 macrophages led to the overexpression of numerous genes linked to tumor growth, angiogenesis, invasion, and immune suppression in NSCLC cells, increasing the BCL2/BAX ratio and promoting cellular resistance to apoptosis. The anti-tumor efficacy of vinorelbine appears to be partly attributed to the reprogramming of M2 macrophages to the M1 phenotype, suggesting that low-dose vinorelbine may optimize therapeutic outcomes while minimizing toxicity in cancer patients.
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Affiliation(s)
- Ahmed Al-Omar
- Department of Basic Oncology, Institute of Health Sciences, Ege University, Bornova 35100, Izmir, Turkey; (A.A.-O.); (M.A.); (C.M.)
| | - Milad Asadi
- Department of Basic Oncology, Institute of Health Sciences, Ege University, Bornova 35100, Izmir, Turkey; (A.A.-O.); (M.A.); (C.M.)
| | - Ufuk Mert
- Atatürk Health Care Vocational School, Ege University, Bornova 35100, Izmir, Turkey;
- Translational Pulmonary Research Group (EGESAM), Ege University, Bornova 35100, Izmir, Turkey; (H.S.K.); (T.G.)
| | - Can Muftuoglu
- Department of Basic Oncology, Institute of Health Sciences, Ege University, Bornova 35100, Izmir, Turkey; (A.A.-O.); (M.A.); (C.M.)
| | - Haydar Soydaner Karakus
- Translational Pulmonary Research Group (EGESAM), Ege University, Bornova 35100, Izmir, Turkey; (H.S.K.); (T.G.)
- Department of Pulmonary Medicine, Faculty of Medicine, Ege University, Bornova 35100, Izmir, Turkey
| | - Tuncay Goksel
- Translational Pulmonary Research Group (EGESAM), Ege University, Bornova 35100, Izmir, Turkey; (H.S.K.); (T.G.)
- Department of Pulmonary Medicine, Faculty of Medicine, Ege University, Bornova 35100, Izmir, Turkey
| | - Ayse Caner
- Department of Basic Oncology, Institute of Health Sciences, Ege University, Bornova 35100, Izmir, Turkey; (A.A.-O.); (M.A.); (C.M.)
- Translational Pulmonary Research Group (EGESAM), Ege University, Bornova 35100, Izmir, Turkey; (H.S.K.); (T.G.)
- Department of Parasitology, Faculty of Medicine, Ege University, Bornova 35100, Izmir, Turkey
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Kim Y, Hur J, Hong SC, Jung J, Park CH, Park JB, Yoon TJ, Kim JB, Yang SH. Modulated electro-hyperthermia therapy combined with Korean mistletoe extract treatment exerts a strong anti-tumor activity by enhancing cellular and humoral immune responses in mice. Anim Cells Syst (Seoul) 2025; 29:163-172. [PMID: 40040867 PMCID: PMC11878165 DOI: 10.1080/19768354.2025.2470455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Revised: 02/04/2025] [Accepted: 02/10/2025] [Indexed: 03/06/2025] Open
Abstract
Electro-hyperthermia therapy (EHT) has been known to cause temperature-dependent cell death and enhance the effects of conventional antitumor treatments, such as chemotherapy and radiotherapy. Furthermore, EHT modulates the innate and adaptive immune systems. Mistletoe is one of the most broadly studied complementary and alternative therapeutic agents for cancer treatment due to its ability to stimulate the immune systems. This study aimed to investigate the effects of EHT and mistletoe therapy combination on immune responses. Tumors induced by B16-BL6 melanoma cells were treated twice with modulated EHT (mEHT) (43°C for 10 or 20 min) and with intravenous injection of a Korean mistletoe extract (KME). We examined the level of interferon (IFN)-γ, granzyme, interleukin (IL)-2, IL-10, and tumor-specific antibodies using enzyme-linked immunosorbent assay methods to further study the immunological responses in the combination of mEHT and KME. Additionally, cytotoxic T lymphocyte (CTL) activity is investigated. In this study, we revealed a significant anti-tumor immunological activity elevation in tumor-bearing mice by combined mEHT and KME therapy. Specifically, the combination of mEHT and KME treatment was effective in inhibiting tumor growth in mice. The combination treatment elicited CTL immune response and increased IFN-γ and granzyme secretion. Particularly, the co-treatment appeared to efficiently suppress the immune signal related to tumor-associated macrophage differentiation. Importantly, tumor cell-specific antibodies could be induced in mice after mEHT-treated tumor cell immunization, which represent a promising cancer vaccine strategy. Thus, our results indicate the therapeutic actions of KME as a feasible partner of mEHT, suggesting its potential candidate for cancer immunotherapy. Abbreviations: APC, Antigen-presenting cell; CTL, Cytotoxic T lymphocyte; EHT, Electro-hyperthermia therapy; ELISA, Enzyme-linked immunosorbent assay; HSP, Heat shock protein; KME, Korean mistletoe extract; NK, Natural killer; PBS, Phosphate-buffered saline; QOL, Quality of life; RF, Radio-frequency; TAM, Tumor-associated macrophage.
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Affiliation(s)
- Yebeen Kim
- Department of Biomedical Engineering, College of Life Science and Biotechnology, Dongguk University, Seoul, Republic of Korea
| | - Jinwoo Hur
- Department of Food and Nutrition, Yuhan University, Buchoen, Republic of Korea
| | - Sung-Chul Hong
- Department of Food Science and Biotechnology, Kunsan National University, Kunsan, Republic of Korea
| | - Jaewoon Jung
- Department of Biomedical Engineering, College of Life Science and Biotechnology, Dongguk University, Seoul, Republic of Korea
| | - Choon-Ho Park
- Graduate School of Clinical Pharmacy and Pharmaceutics, Ajou University, Suwon, South Korea
| | - Joon Beom Park
- Mistletoe Research Center, New Breath Hospital, Seoul, Republic of Korea
| | | | - Jong Bae Kim
- Mistletoe Research Center, New Breath Hospital, Seoul, Republic of Korea
| | - Seung-Hoon Yang
- Department of Biomedical Engineering, College of Life Science and Biotechnology, Dongguk University, Seoul, Republic of Korea
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Ni H, Reitman ZJ, Zou W, Akhtar MN, Paul R, Huang M, Zhang D, Zheng H, Zhang R, Ma R, Ngo G, Zhang L, Diffenderfer ES, Motlagh SAO, Kim MM, Minn AJ, Dorsey JF, Foster JB, Metz J, Koumenis C, Kirsch DG, Gong Y, Fan Y. FLASH radiation reprograms lipid metabolism and macrophage immunity and sensitizes medulloblastoma to CAR-T cell therapy. NATURE CANCER 2025; 6:460-473. [PMID: 39910249 DOI: 10.1038/s43018-025-00905-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Accepted: 01/07/2025] [Indexed: 02/07/2025]
Abstract
FLASH radiotherapy holds promise for treating solid tumors given the potential lower toxicity in normal tissues but its therapeutic effects on tumor immunity remain largely unknown. Using a genetically engineered mouse model of medulloblastoma, we show that FLASH radiation stimulates proinflammatory polarization in tumor macrophages. Single-cell transcriptome analysis shows that FLASH proton beam radiation skews macrophages toward proinflammatory phenotypes and increases T cell infiltration. Furthermore, FLASH radiation reduces peroxisome proliferator-activated receptor-γ (PPARγ) and arginase 1 expression and inhibits immunosuppressive macrophage polarization under stimulus-inducible conditions. Mechanistically, FLASH radiation abrogates lipid oxidase expression and oxidized low-density lipid generation to reduce PPARγ activity, while standard radiation induces reactive oxygen species-dependent PPARγ activation in macrophages. Notably, FLASH radiotherapy improves infiltration and activation of chimeric antigen receptor (CAR) T cells and sensitizes medulloblastoma to GD2 CAR-T cell therapy. Thus, FLASH radiotherapy reprograms macrophage lipid metabolism to reverse tumor immunosuppression. Combination FLASH-CAR radioimmunotherapy may offer exciting opportunities for solid tumor treatment.
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Affiliation(s)
- Haiwei Ni
- Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA, USA
| | - Zachary J Reitman
- Department of Radiation Oncology, Duke University Medical Center, Durham, NC, USA
| | - Wei Zou
- Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA, USA
| | - Md Naushad Akhtar
- Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA, USA
| | - Ritama Paul
- Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA, USA
| | - Menggui Huang
- Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA, USA
| | - Duo Zhang
- Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA, USA
| | - Hao Zheng
- Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA, USA
| | - Ruitao Zhang
- Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA, USA
| | - Ruiying Ma
- Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA, USA
| | - Gina Ngo
- Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA, USA
| | - Lin Zhang
- Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, PA, USA
| | - Eric S Diffenderfer
- Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA, USA
| | | | - Michele M Kim
- Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA, USA
| | - Andy J Minn
- Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA, USA
- Mark Foundation Center for Immunotherapy, Immune Signaling, and Radiation, University of Pennsylvania, Philadelphia, PA, USA
| | - Jay F Dorsey
- Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA, USA
| | - Jessica B Foster
- Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - James Metz
- Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA, USA
| | - Constantinos Koumenis
- Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA, USA
- Mark Foundation Center for Immunotherapy, Immune Signaling, and Radiation, University of Pennsylvania, Philadelphia, PA, USA
| | - David G Kirsch
- Department of Radiation Oncology, Duke University Medical Center, Durham, NC, USA.
- Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
- Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada.
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
| | - Yanqing Gong
- Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
| | - Yi Fan
- Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA, USA.
- Mark Foundation Center for Immunotherapy, Immune Signaling, and Radiation, University of Pennsylvania, Philadelphia, PA, USA.
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Altıntaş E, Şahin A, Erol S, Özer H, Gül M, Batur AF, Kaynar M, Kılıç Ö, Göktaş S. Navigating the gray zone: Machine learning can differentiate malignancy in PI-RADS 3 lesions. Urol Oncol 2025; 43:195.e11-195.e20. [PMID: 39343658 DOI: 10.1016/j.urolonc.2024.09.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Revised: 08/21/2024] [Accepted: 09/05/2024] [Indexed: 10/01/2024]
Abstract
INTRODUCTION The objective of this study is to predict the probability of prostate cancer in PI-RADS 3 lesions using machine learning methods that incorporate clinical and mpMRI parameters. METHODS The study included patients who had PI-RADS 3 lesions detected on mpMRI and underwent fusion biopsy between January 2020 and January 2024. Radiological parameters (Apparent diffusion coefficient (ADC), tumour ADC/contralateral ADC ratio, Ktrans value, periprostatic adipose tissue thickness, lesion size, prostate volume) and clinical parameters (age, body mass index, total prostate specific antigen, free PSA, PSA density, systemic inflammatory index, neutrophil-lymphocyte ratio [NLR], platelet lymphocyte ratio, lymphocyte monocyte ratio) were documented. The probability of prostate cancer prediction in PI-RADS 3 lesions was calculated using 6 different machine-learning models, with the input parameters being the aforementioned variables. RESULTS Of the 235 participants in the trial, 61 had malignant fusion biopsy pathology and 174 had benign pathology. Among 6 different machine learning algorithms, the random forest model had the highest accuracy (0.86±0.04; 95% CI 0.85-0.87), F1 score (0.91±0.03; 95% CI 0.91-0.92) and AUC value (0.92±0.06; 95% CI 0.88-0.90). In SHAP analysis based on random forest model, tumour ADC, tumour ADC/contralateral ADC ratio and PSA density were the 3 most successful parameters in predicting malignancy. On the other hand, systemic inflammatory index and neutrophil lymphocyte ratio showed higher accuracy in predicting malignancy than total PSA, age, free PSA/total PSA and lesion size in SHAP analysis. CONCLUSION Among the machine learning models we developed, especially the random forest model can predict malignancy in PI-RADS 3 lesions and prevent unnecessary biopsy. This model can be used in clinical practice with multicentre studies including more patients.
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Affiliation(s)
- Emre Altıntaş
- Department of Urology, Selcuk University School of Medicine, Konya, Turkey.
| | - Ali Şahin
- Selcuk University School of Medicine, Konya, Turkey
| | - Seyit Erol
- Department of Radiology, Selcuk University School of Medicine, Konya, Turkey
| | - Halil Özer
- Department of Radiology, Selcuk University School of Medicine, Konya, Turkey
| | - Murat Gül
- Department of Urology, Selcuk University School of Medicine, Konya, Turkey
| | - Ali Furkan Batur
- Department of Urology, Selcuk University School of Medicine, Konya, Turkey
| | - Mehmet Kaynar
- Department of Urology, Selcuk University School of Medicine, Konya, Turkey
| | - Özcan Kılıç
- Department of Urology, Selcuk University School of Medicine, Konya, Turkey
| | - Serdar Göktaş
- Department of Urology, Selcuk University School of Medicine, Konya, Turkey
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28
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Zhang M, Wei J, Sun Y, He C, Ma S, Pan X, Zhu X. The efferocytosis process in aging: Supporting evidence, mechanisms, and therapeutic prospects for age-related diseases. J Adv Res 2025; 69:31-49. [PMID: 38499245 PMCID: PMC11954809 DOI: 10.1016/j.jare.2024.03.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2023] [Revised: 03/11/2024] [Accepted: 03/13/2024] [Indexed: 03/20/2024] Open
Abstract
BACKGROUND Aging is characterized by an ongoing struggle between the buildup of damage caused by a combination of external and internal factors. Aging has different effects on phagocytes, including impaired efferocytosis. A deficiency in efferocytosis can cause chronic inflammation, aging, and several other clinical disorders. AIM OF REVIEW Our review underscores the possible feasibility and extensive scope of employing dual targets in various age-related diseases to reduce the occurrence and progression of age-related diseases, ultimately fostering healthy aging and increasing lifespan. Key scientific concepts of review Hence, the concurrent implementation of strategies aimed at augmenting efferocytic mechanisms and anti-aging treatments has the potential to serve as a potent intervention for extending the duration of a healthy lifespan. In this review, we comprehensively discuss the concept and physiological effects of efferocytosis. Subsequently, we investigated the association between efferocytosis and the hallmarks of aging. Finally, we discuss growing evidence regarding therapeutic interventions for age-related disorders, focusing on the physiological processes of aging and efferocytosis.
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Affiliation(s)
- Meng Zhang
- Department of Neurology, The Affiliated Hospital of Qingdao University, Qingdao 266000, China
| | - Jin Wei
- Department of Neurology, The Affiliated Hospital of Qingdao University, Qingdao 266000, China
| | - Yu Sun
- Department of Neurology, The Affiliated Hospital of Qingdao University, Qingdao 266000, China
| | - Chang He
- Department of Critical Care Medicine, The Affiliated Hospital of Qingdao University, Qingdao 266000, China
| | - Shiyin Ma
- Department of Neurology, The Affiliated Hospital of Qingdao University, Qingdao 266000, China
| | - Xudong Pan
- Department of Neurology, The Affiliated Hospital of Qingdao University, Qingdao 266000, China.
| | - Xiaoyan Zhu
- Department of Critical Care Medicine, The Affiliated Hospital of Qingdao University, Qingdao 266000, China.
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Fang J, Wang J, Zhao X, Yang Y, Xiao Y. KLHDC8A knockdown in normal ovarian epithelial cells promoted the polarization of pro-tumoral macrophages via the C5a/C5aR/p65 NFκB signaling pathway. Cell Immunol 2025; 409-410:104913. [PMID: 39805213 DOI: 10.1016/j.cellimm.2024.104913] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Revised: 12/13/2024] [Accepted: 12/22/2024] [Indexed: 01/16/2025]
Abstract
AIMS Tumor-associated macrophages (TAM) is related to Ovarian cancer (OC) pathogenesis, but the exact mechanism remains unclear. This study investigated the expression of Kelch Domain Containing 8 A (KLHDC8A) in OC and the mechanism associated with TAM. MAIN METHODS Bioinformatics analysis of differential expression genes between normal and OC tissues were analyzed based on the Tumor Genome Atlas (TCGA) databases. KLHDC8A mRNA expression was knocked down in normal epithelial cells (IOSE80), and then the effects of siKLHDC8A on the proliferation, invasion, migration and C5a secretion of IOSE80 cells were explored. THP1-derived macrophages were cultured with medium of NC-IOSE80 cells, siKLHDC8A-IOSE80 cells with or without C5aR antagonists. KEY FINDINGS KLHDC8A was lowly expressed in OC and negatively correlated with the infiltration of tumor-promoting macrophages, contributing to the survival of OC patients. Furthermore, siKLHDC8A promotes the proliferation, invasion and migration of IOSE80 cells and leads to polarization of pro-tumoral macrophages, which can be rescued by C5aR antagonists. SIGNIFICANCE Our results indicated that KLHDC8A knockdown could modulate the development of OC by affecting macrophage polarization to pro-tumoral type via the C5a/C5aR/p65 NFκB signaling pathway. It may play an essential role as the tumor suppressor genes in diagnosis and treatment of OC.
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Affiliation(s)
- Jie Fang
- Department of Gynecology, the Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang, Jiangsu 212001, China.
| | - Jin Wang
- Department of Gynecology, the Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang, Jiangsu 212001, China
| | - Xinyue Zhao
- Department of Gynecology, the Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang, Jiangsu 212001, China
| | - Yaping Yang
- Department of Gynecology, the Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang, Jiangsu 212001, China
| | - Yujia Xiao
- Department of Gynecology, the Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang, Jiangsu 212001, China
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Teng F, Wei H, Che D, Miao K, Dong X. Identifying macrophage-associated subtypes in patients with serous ovarian cancer and exploring potential personalized therapeutic drugs using combined single-cell and bulk RNA sequencing omics. Heliyon 2025; 11:e42429. [PMID: 40028569 PMCID: PMC11870195 DOI: 10.1016/j.heliyon.2025.e42429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 01/14/2025] [Accepted: 01/31/2025] [Indexed: 03/05/2025] Open
Abstract
Purpose We aimed to analyze the sensitivity of patients to chemotherapy drugs and actively explore potential new intervention targets, providing an essential reference for personalized treatment. Methods Candidate markers with significant differential expression in macrophages were identified by analyzing gene expression at the single-cell level. A weighted gene co-expression network (WGCN) was constructed on the GSE26712 dataset to explore the modules most relevant to macrophages. Differentially expressed genes for specific markers were identified. A multi-factor regulatory network was constructed based on single-cell dataset markers screening, differentially expressed genes, and genes commonly present in WGCNA modules. Different macrophage subtypes were identified using this network. Machine learning was used to filter and predict the markers' drug sensitivity, and the potential therapeutic compounds for specific markers were screened. Results We identified 14 and 17 of M1 and M2 macrophage candidate markers, respectively. In the multi-factor regulatory network of M1 macrophages, 6 out of 14 markers recognized 159 transcription factors (TFs) and 48 micro RNAs (miRNAs), whereas 13 of 17 markers recognized 191 TFs and 182 miRNAs in the multi-factor regulatory network of M2 macrophages. Filtering of the identified differentially expressed genes using random forests yielded 15 M1 and M2 macrophage-specific markers. Drug sensitivity prediction analysis and in vitro experiments revealed the close association of these markers with common chemotherapy drug sensitivity. Conclusion We identified specific M1 and M2 macrophage markers and found potential therapeutic compounds (dasatinib and afatinib) in these specific markers. These potential therapeutic compounds provide insight into the underlying mechanisms of serous ovarian cancer (OC) and inspire more effective treatment methods.
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Affiliation(s)
- Fei Teng
- In-Patient Ultrasound Department, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
- Ultrasound Department, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Hong Wei
- In-Patient Ultrasound Department, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Dehong Che
- Ultrasound Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Kuo Miao
- Ultrasound Department, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xiaoqiu Dong
- Ultrasound Department, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
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Wu DH, Qiu HC, Xu J, Lin J, Qian J. Hypomethylation of GCNT2 isoform A correlates with transcriptional expression and is associated with poor survival in acute myeloid leukemia. Front Immunol 2025; 16:1490330. [PMID: 40034691 PMCID: PMC11873079 DOI: 10.3389/fimmu.2025.1490330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Accepted: 01/27/2025] [Indexed: 03/05/2025] Open
Abstract
Background The function of GCNT2 has been documented to act as an oncogenic driver or tumor suppressor in different types of tumor, but the role of GCNT2 and the epigenetic regulation mechanism in AML, however, has not yet been clarified. This study aimed to assay the expression and methylation profile of GCNT2 in AML, and further elucidate the clinical significance. Methods Multiple datasets from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas projects (TCGA) were used to explore the expression and methylation profile of GCNT2 in normal hematopoiesis and AML. A pan-cancer analysis was performed to define the survival implications of GCNT2 across multiple cancers including AML. The relationships between GCNT2 expression/methylation and clinicopathologic features were investigated using a TCGA-AML dataset. Correlation analysis was performed to explore the relationship between transcriptional expression and DNA methylation. Differentially expressed genes (DEGs) on the KEGG pathway and GO terms were visualized using DAVID. Gene Set Enrichment Analysis (GESA) was carried out to assess the underlying mechanism. The relationship between methylation and immune cell infiltration was also examined. Results GCNT2 expression was highest in hematopoietic stem cells (HSC) but gradually decreased during the hematopoiesis differentiation, the monocytes, however, remained a high level of GCNT2 as an exception. In AML, GCNT2 was down-regulated as compared to normal hematopoiesis but was much higher in contrast to normal peripheral blood samples. Data from a pan-cancer analysis revealed that high-expressed GCNT2 contributed to a worse OS for AML. DNA methylation of GCNT2 showed a distinctive co-methylation pattern in AML and significantly negatively correlated with transcriptional expression. Methylation in the transcriptional start site of isoform A plays a critical role in the epigenetic regulation of GCNT2 expression. The silence of GCNT2 in AML was attributed to DNA methylation. Hypomethylation of isoform A significantly predicted poor survival in AML, linking to several cytogenetic and molecular abnormalities, such as t (8:21), inv (16), t (15;17), and genes mutations of DNMT3A, CEBPA, RUNX1, and WT1. Enrichment analysis disclosed that hypomethylation of isoform A was involved in the immune system, and it was further revealed that hypomethylation of isoform A was tightly associated with immune cell infiltration and could be served as a promising indicator for immunotherapy. Conclusions Our comprehensive research demonstrated that GCNT2 acted as an oncogene in AML, and was epigenetically regulated by DNA methylation in isoform A. Hypomethylation of isoform A could be served as a promising indicator to identify the high-risk AML patients who might be responsive to immunotherapy.
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MESH Headings
- Humans
- Leukemia, Myeloid, Acute/genetics
- Leukemia, Myeloid, Acute/mortality
- Leukemia, Myeloid, Acute/immunology
- Leukemia, Myeloid, Acute/pathology
- DNA Methylation
- Gene Expression Regulation, Leukemic
- Protein Isoforms/genetics
- Prognosis
- Female
- Epigenesis, Genetic
- Male
- Gene Expression Profiling
- Middle Aged
- Biomarkers, Tumor/genetics
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Affiliation(s)
- De-hong Wu
- Deparrtment of Central Lab, Affiliated People’s Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
- Deparrtment of Hematology, KunShan Third People’s Hospital, Kunshan, Jiangsu, China
| | - Hong-chun Qiu
- Deparrtment of Hematology, KunShan Third People’s Hospital, Kunshan, Jiangsu, China
| | - Jing Xu
- Deparrtment of Hematology, KunShan Third People’s Hospital, Kunshan, Jiangsu, China
| | - Jiang Lin
- Deparrtment of Central Lab, Affiliated People’s Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Jun Qian
- Deparrtment of Central Lab, Affiliated People’s Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
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Yang Y, Li W, Zhao Y, Sun M, Xing F, Yang J, Zhou Y. GRP78 in Glioma Progression and Therapy: Implications for Targeted Approaches. Biomedicines 2025; 13:382. [PMID: 40002794 PMCID: PMC11852679 DOI: 10.3390/biomedicines13020382] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2024] [Revised: 01/24/2025] [Accepted: 02/03/2025] [Indexed: 02/27/2025] Open
Abstract
Glioma is the most common primary malignant brain tumor, accounting for the majority of brain cancer-related deaths. Considering the limited efficacy of conventional therapies, novel molecular targeted therapies have been developed to improve outcomes and minimize toxicity. Glucose-regulated protein 78 (GRP78), a molecular chaperone primarily localized in the endoplasmic reticulum (ER), has received increasing attention for its role in glioma progression and resistance to conventional therapies. Overexpressed in gliomas, GRP78 supports tumor growth, survival, and therapeutic resistance by maintaining cellular homeostasis and regulating multiple signaling pathways. Its aberrant expression correlates with higher tumor grades and poorer patient prognosis. Beyond its intracellular functions, GRP78's presence on the cell surface and its role in the tumor microenvironment underscore its potential as a therapeutic target. Recent studies have explored innovative strategies to target GRP78, including small molecule inhibitors, monoclonal antibodies, and chimeric antigen receptor (CAR) T cell therapy, showing significant potential in glioma treatment. This review explores the biological characteristics of GRP78, its role in glioma pathophysiology, and the potential of GRP78-targeted therapy as a novel strategy to overcome treatment resistance and improve clinical outcomes. GRP78-targeted therapy, either alone or in combination with conventional treatments, could be a novel and attractive strategy for future glioma treatment.
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Affiliation(s)
- Yue Yang
- Department of Chemistry, College of Sciences, Shanghai University, Shanghai 200444, China
| | - Wen Li
- School of Biomedical Engineering (Suzhou), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China; (W.L.); (Y.Z.)
- Department of Biomaterials and Stem Cells, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou 215163, China
| | - Yu Zhao
- School of Biomedical Engineering (Suzhou), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China; (W.L.); (Y.Z.)
- Department of Biomaterials and Stem Cells, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou 215163, China
| | - Minxuan Sun
- School of Biomedical Engineering (Suzhou), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China; (W.L.); (Y.Z.)
- Department of Biomaterials and Stem Cells, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou 215163, China
| | - Feifei Xing
- Department of Chemistry, College of Sciences, Shanghai University, Shanghai 200444, China
| | - Jiao Yang
- Suzhou Research Center of Medical School, Institute of Clinical Medicine Research, Suzhou Hospital, The Affiliated Hospital of Medical School, Nanjing University, Lijiang Road No. 1, Suzhou 215153, China
- Jiangsu Province Engineering Research Center of Molecular Target Therapy and Companion Diagnostics in Oncology, Suzhou Vocational Health College, Suzhou 215009, China
| | - Yuanshuai Zhou
- School of Biomedical Engineering (Suzhou), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China; (W.L.); (Y.Z.)
- Department of Biomaterials and Stem Cells, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou 215163, China
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Qi X, Lian Y, Fan Z, Wang H, Jiang H, He M, Li L, Huang J, Wan Y. Electroacupuncture normalized tumor vasculature by downregulating glyoxalase-1 to polarize tumor-associated macrophage to M1 phenotype in triple-negative breast cancer. Int Immunopharmacol 2025; 147:113988. [PMID: 39778275 DOI: 10.1016/j.intimp.2024.113988] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Revised: 12/18/2024] [Accepted: 12/28/2024] [Indexed: 01/11/2025]
Abstract
BACKGROUND Triple-negative breast cancer is a particularly aggressive type of breast cancer that is closely associated with abnormal vascularization within the tumor. However, traditional anti-VEGF therapies and other treatments have limited efficacy. Tumor-associated macrophages (TAMs) induce and regulate tumor angiogenesis. In recent years, regulating TAMs polarization has become a hot topic for research with objectives to normalize tumor vasculature and improve drug delivery and the tumor microenvironment. Our previous studies have found that peritumoral electroacupuncture (EA) can regulate tumor angiogenesis, but the underlying mechanism remains unclear. METHODS In this study, we examined the phenotype of TAMs and inflammatory factors to observe the effect of peritumoral electroacupuncture on the phenotypic polarization of TAMs. Based on this, we evaluated the structure and function of tumor vasculature. Finally, we conducted a preliminary exploration of the mechanism underlying the regulation of TAMs phenotypic polarization by peritumoral electroacupuncture. RESULTS In this study, we found that peritumoral electroacupuncture could promote the phenotypic polarization of TAMs toward the M1 type, thereby reducing microvascular density in tumor tissue, increasing pericyte coverage, improving the stability of the basement membrane, promoting vascular maturation, and enhancing perfusion while reducing tissue hypoxia. CONCLUSIONS Peritumoral electroacupuncture can promote the phenotypic polarization of TAMs toward the M1 type, leading to normalization of tumor vascular structure and function. The mechanism may be related to the downregulation of glyoxalase-1 and subsequent activation of the MGO-AGEs/RAGE axis.
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Affiliation(s)
- Xuewei Qi
- Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
| | - Yanyan Lian
- Chaoyang District Hospital of Traditional Chinese Medicine, Beijing, China
| | - Zhenjia Fan
- Beijing University of Chinese Medicine, Beijing, China
| | - Hui Wang
- The Third Affiliated Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Honglin Jiang
- The Third Affiliated Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Mengyang He
- The Third Affiliated Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Liling Li
- The Third Affiliated Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Jinchang Huang
- The Third Affiliated Hospital, Beijing University of Chinese Medicine, Beijing, China.
| | - Yuxiang Wan
- The Third Affiliated Hospital, Beijing University of Chinese Medicine, Beijing, China.
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Shah S, Osuala KO, Brock EJ, Ji K, Sloane BF, Mattingly RR. Three-Dimensional Models: Biomimetic Tools That Recapitulate Breast Tissue Architecture and Microenvironment to Study Ductal Carcinoma In Situ Transition to Invasive Ductal Breast Cancer. Cells 2025; 14:220. [PMID: 39937011 PMCID: PMC11817749 DOI: 10.3390/cells14030220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2024] [Revised: 01/30/2025] [Accepted: 01/31/2025] [Indexed: 02/13/2025] Open
Abstract
Diagnosis of ductal carcinoma in situ (DCIS) presents a challenge as we cannot yet distinguish between those lesions that remain dormant from cases that may progress to invasive ductal breast cancer (IDC) and require therapeutic intervention. Our overall interest is to develop biomimetic three-dimensional (3D) models that more accurately recapitulate the structure and characteristics of pre-invasive breast cancer in order to study the underlying mechanisms driving malignant progression. These models allow us to mimic the microenvironment to investigate many aspects of mammary cell biology, including the role of the extracellular matrix (ECM), the interaction between carcinoma-associated fibroblasts (CAFs) and epithelial cells, and the dynamics of cytoskeletal reorganization. In this review article, we outline the significance of 3D culture models as reliable pre-clinical tools that mimic the in vivo tumor microenvironment and facilitate the study of DCIS lesions as they progress to invasive breast cancer. We also discuss the role of CAFs and other stromal cells in DCIS transition as well as the clinical significance of emerging technologies like tumor-on-chip and co-culture models.
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Affiliation(s)
- Seema Shah
- Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, USA; (S.S.); (E.J.B.)
| | | | - Ethan J. Brock
- Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, USA; (S.S.); (E.J.B.)
| | - Kyungmin Ji
- Department of Neurology, Henry Ford Health, Detroit, MI 48202, USA
- Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI 48201, USA
| | - Bonnie F. Sloane
- Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, USA; (S.S.); (E.J.B.)
- Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI 48201, USA
| | - Raymond R. Mattingly
- Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI 48201, USA
- Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA
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35
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Li Z, Jiang S, Wang J, Li W, Yang J, Liu W, Gao H, Huang Y, Ruan S. Peptide-drug conjugates repolarize glioblastoma-associated macrophages to resensitize chemo-immunotherapy of glioblastoma. SCIENCE ADVANCES 2025; 11:eadr8841. [PMID: 39823328 PMCID: PMC11740939 DOI: 10.1126/sciadv.adr8841] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Accepted: 12/17/2024] [Indexed: 01/19/2025]
Abstract
The prevalent tumor-supporting glioblastoma-associated macrophages (GAMs) promote glioblastoma multiforme (GBM) progression and resistance to multiple therapies. Repolarizing GAMs from tumor-supporting to tumor-inhibiting phenotype may troubleshoot. However, sufficient accumulation of drugs at the GBM site is restricted by blood-brain barrier (BBB). Herein, we designed peptide-drug conjugates (PDCs) by conjugating camptothecin or resiquimod to a tandem peptide composed of matrix metalloproteinase 2-responsive peptide and angiopep-2 via disulfonyl-ethyl carbonate/carbamate (MAPDCs). The mixed self-assembly MAPDCs could recognize low-density lipoprotein receptor-related protein 1 (LRP1) to facilitate BBB transport. Once reaching the GBM site, the responsive peptide would be cleaved to shed the angiopep-2, blocking abluminal LRP1-mediated brain-to-blood efflux and enhancing drug retention. Sequentially, drugs are released under the high level of intracellular glutathione. In vivo studies demonstrated that MAPDCs repolarized GAMs, boosted immune response, and resensitized chemotherapeutic toxicity, offering a much-improved anti-GBM effect. The effectiveness of MAPDCs validates GAMs as therapeutic target and PDCs as versatile brain delivery system with high design flexibility.
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Affiliation(s)
- Zhi Li
- School of Life Science, Beijing Institute of Technology, Beijing 100081, China
- Advanced Research Institute of Multidisciplinary Science, Beijing Institute of Technology, Beijing 100081, China
| | - Shaoping Jiang
- School of Life Science, Beijing Institute of Technology, Beijing 100081, China
- Advanced Research Institute of Multidisciplinary Science, Beijing Institute of Technology, Beijing 100081, China
| | - Jie Wang
- School of Life Science, Beijing Institute of Technology, Beijing 100081, China
- Advanced Research Institute of Multidisciplinary Science, Beijing Institute of Technology, Beijing 100081, China
| | - Wenpei Li
- School of Life Science, Beijing Institute of Technology, Beijing 100081, China
- Advanced Research Institute of Multidisciplinary Science, Beijing Institute of Technology, Beijing 100081, China
| | - Jun Yang
- School of Life Science, Beijing Institute of Technology, Beijing 100081, China
- Advanced Research Institute of Multidisciplinary Science, Beijing Institute of Technology, Beijing 100081, China
| | - Weimin Liu
- School of Life Science, Beijing Institute of Technology, Beijing 100081, China
- Advanced Research Institute of Multidisciplinary Science, Beijing Institute of Technology, Beijing 100081, China
| | - Huile Gao
- West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Yuanyu Huang
- School of Life Science, Beijing Institute of Technology, Beijing 100081, China
- Advanced Research Institute of Multidisciplinary Science, Beijing Institute of Technology, Beijing 100081, China
| | - Shaobo Ruan
- School of Life Science, Beijing Institute of Technology, Beijing 100081, China
- Advanced Research Institute of Multidisciplinary Science, Beijing Institute of Technology, Beijing 100081, China
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Liu Y, Han J, Hsu WH, LaBella KA, Deng P, Shang X, de Lara PT, Cai L, Jiang S, DePinho RA. Combined KRAS Inhibition and Immune Therapy Generates Durable Complete Responses in an Autochthonous PDAC Model. Cancer Discov 2025; 15:162-178. [PMID: 39348506 PMCID: PMC11858029 DOI: 10.1158/2159-8290.cd-24-0489] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 08/27/2024] [Accepted: 09/26/2024] [Indexed: 10/02/2024]
Abstract
SIGNIFICANCE Clinically available KRAS* inhibitors and IO agents alleviated the immunosuppressive tumor microenvironment in PDAC. Profound tumor regression and prolonged survival in an autochthonous PDAC model provide a compelling rationale for combining KRAS* inhibition with IO agents targeting multiple arms of the immunity cycle to combat PDAC.
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Affiliation(s)
- Yonghong Liu
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030 USA
| | - Jincheng Han
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030 USA
| | - Wen-Hao Hsu
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030 USA
| | - Kyle A. LaBella
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030 USA
| | - Pingna Deng
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030 USA
| | - Xiaoying Shang
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030 USA
| | - Paulino Tallón de Lara
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030 USA
| | - Li Cai
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030 USA
| | - Shan Jiang
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030 USA
| | - Ronald A. DePinho
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030 USA
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Shabo I, Midtbö K, Bränström R, Lindström A. Monocyte-cancer cell fusion is mediated by phosphatidylserine-CD36 receptor interaction and induced by ionizing radiation. PLoS One 2025; 20:e0311027. [PMID: 39752516 PMCID: PMC11698428 DOI: 10.1371/journal.pone.0311027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Accepted: 09/11/2024] [Indexed: 01/06/2025] Open
Abstract
Emerging evidence suggests that fusion of cancer cells with leucocytes, such as macrophages, plays a significant role in cancer metastasis and results in tumor hybrid cells that acquire resistance to chemo- and radiation therapy. However, the precise mechanisms behind the leukocyte-cancer cell fusion remain unclear. The present in vitro study explores the presence of fusion between the monocyte cell line (THP-1) and the breast cancer cell line (MCF-7) in relation to the expression of CD36 and phosphatidylserine with and without treatment of these cells with ionizing radiation. The study reveals that spontaneous THP-1/MCF-7 cell fusion increases significantly from 2.8% to 6% after irradiation. The interaction between CD36 and phosphatidylserine plays a pivotal role in THP-1/MCF-7 cell fusion, as inhibiting this interaction using anti-CD36 antibodies significantly reduces cell fusion. While irradiation leads to a dose-dependent escalation in phosphatidylserine expression in MCF-7 cells, it does not impact the expression of CD36 in either THP-1 or MCF-7 cells. To the best of our knowledge, this is the first study to demonstrate the involvement of the CD36-phosphatidylserine interaction in the fusion between monocytes and cancer cells, shedding light on a novel explanatory mechanism for the roles of CD36 and phosphatidylserine in tumor progression.
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Affiliation(s)
- Ivan Shabo
- Endocrine and Sarcoma Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Department of Breast Cancer, Sarcoma and Endocrine Tumors, Theme Cancer, Karolinska University Hospital, Stockholm, Sweden
| | - Kristine Midtbö
- Division of Cell- and Neurobiology, Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden
| | - Robert Bränström
- Endocrine and Sarcoma Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Department of Breast Cancer, Sarcoma and Endocrine Tumors, Theme Cancer, Karolinska University Hospital, Stockholm, Sweden
| | - Annelie Lindström
- Division of Cell- and Neurobiology, Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden
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38
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Rivas CH, Liu F, Zhang XHF. The Roles of Myeloid Cells in Breast Cancer Progression. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2025; 1464:397-412. [PMID: 39821035 DOI: 10.1007/978-3-031-70875-6_19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/19/2025]
Abstract
This chapter reviews tumor-associated myeloid cells, including macrophages, neutrophils, and other innate immune cells, and their multifaceted roles in supporting breast cancer progression and metastasis. In primary tumors, myeloid cells play key roles in promoting tumor epithelial-mesenchymal transition (EMT) and invasion. They can facilitate intravasation (entry into the bloodstream) and colonization, disrupting the endothelial cell layer and reshaping the extracellular matrix. They can also stimulate angiogenesis, suppress immune cell responses, and enhance cancer cell adaptability. In the bloodstream, circulating myeloid cells enable the survival of disseminated tumor cells via immunosuppressive effects and physical shielding. At the metastatic sites, they prime the premetastatic niche, facilitate tumor cell extravasation, and support successful colonization and outgrowth. Mechanistically, myeloid cells enhance cancer cell survival, dormancy escape, proliferation, and mesenchymal-epithelial transition (MET). Nonetheless, substantial gaps in our understanding persist regarding the functional and spatiotemporal diversity, as well as the evolutionary patterns, of myeloid cells during metastatic progression. Myeloid cell plasticity and differential responses to therapies present key barriers to successful treatments. Identifying specific pro-tumoral myeloid cell subpopulations and disrupting their interactions with cancer cells represent promising therapeutic opportunities. Emerging evidence suggests combining immunomodulators or stromal normalizers with conventional therapies could help overcome therapy-induced immunosuppression and improve patient outcomes. Overall, further elucidating myeloid cell heterogeneity and function throughout the process of breast cancer progression and metastasis will enable more effective therapeutic targeting of these critical stromal cells.
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Affiliation(s)
- Charlotte Helena Rivas
- Cancer and Cell Biology Program, Graduate School of Biomedical Sciences, San Antonio, TX, USA
| | - Fengshuo Liu
- Cancer and Cell Biology Program, Graduate School of Biomedical Sciences, San Antonio, TX, USA
| | - Xiang H-F Zhang
- Lester and Sue Smith Breast Center, Houston, TX, USA.
- Department of Molecular and Cellular Biology, Berkeley, CA, USA.
- Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA.
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Guo S, Wang L, Bu D, Liu F. Tumors in the setting of dupilumab use: A review of the literature. World Allergy Organ J 2025; 18:101006. [PMID: 39758935 PMCID: PMC11697539 DOI: 10.1016/j.waojou.2024.101006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Revised: 08/22/2024] [Accepted: 11/11/2024] [Indexed: 01/07/2025] Open
Abstract
Dupilumab is the first monoclonal antibody approved for treating moderate-to-severe atopic dermatitis (AD) and has significantly improved the quality of life of AD patients. However, the safety of dupilumab is yet unclear in the context of cancer. Therefore, we aimed to investigate the safety of dupilumab and its relationship with the progression and occurrence of tumors. By reviewing relevant medical records of 90 patients who had pre-existing tumors before dupilumab treatment or presented new tumors after dupilumab treatment, we found that dupilumab probably had no significant negative effects on most tumors, but several patients with Cutaneous T-cell lymphomas (CTCLs) had relatively unfavorable outcomes during dupilumab treatment. Besides, CTCLs and lymphomas accounted for the majority of patients who presented new tumors after dupilumab treatment. Several patients were first diagnosed with presumed AD and probably were the presentations of CTCL at an early stage, and they developed typical CTCL symptoms after dupilumab treatment. Finally we came to the conclusion that dupilumab is safe for most patients with cancer. However, the effect of dupilumab on CTCLs is disputable. The use of dupilumab requires individual evaluation and closely monitored. When the efficacy is poor, re-evaluation of the diagnosis, especially of CTCLs and related diseases, is necessary.
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Affiliation(s)
- Shumeng Guo
- Department of Dermatology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, China
| | - Liangchun Wang
- Department of Dermatology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, China
| | - Dingfang Bu
- Department of Dermatology, Peking University First Hospital, Beijing, China
| | - Fengjie Liu
- Department of Dermatology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, China
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40
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Gong J, Cheng D, Liu C, Wu S, Sun N, Zhao L, Li J, Xing Y, Zhao J. Hybrid Cell Membrane-Coated Nanoparticles for Synergizing Sonodynamic Therapy and Immunotherapy against Triple-Negative Breast Cancer. Adv Healthc Mater 2025; 14:e2404184. [PMID: 39573837 DOI: 10.1002/adhm.202404184] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Revised: 11/12/2024] [Indexed: 01/29/2025]
Abstract
Tumor immunotherapy represents a highly promising modality for the treatment of triple-negative breast cancer (TNBC). Nevertheless, its therapeutic efficacy has been profoundly impacted by challenges such as low drug uptake, hypoxia, and immunosuppression. To address these problems, the study develops a strategy combining sonodynamic therapy (SDT) and immunotherapy using biomimetic nanoparticles coated with hybrid membranes. The nanoparticles are loaded with semiconducting polymers (PFODBT), Atovaquone (ATO), and TMP195 to enhance biocompatibility, targeting ability, and drug uptake and retention at the tumor site. In in vitro experiments, the biomimetic nanoparticles alleviate hypoxia, induce immunogenic cell death (ICD), and prompt reprogramming of tumor-associated macrophages (TAMs) from M2 type to M1 type. In in vivo experiments, the synergistic effects of enhanced SDT-mediated ICD and TAMs repolarization significantly inhibit the proliferation of primary and distant tumor in the 4T1 subcutaneous tumor model, and effectively attenuated metastasis of lung and liver. Moreover, the in vivo immune responses are further activated by improving the maturation of dendritic cells, filtration of CD8+ T cells, and depletion of regulatory T cells. This study offers a novel strategy for TNBC therapy by converting the tumor microenvironment from the "cold" into "hot" tumor through multiple synergistic therapies.
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Affiliation(s)
- Jiali Gong
- Department of Nuclear Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
| | - Danling Cheng
- State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Biological Science and Medical Engineering, Donghua University, Shanghai, 201620, China
| | - Changcun Liu
- Department of Nuclear Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
| | - Shan Wu
- Department of Nuclear Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
| | - Na Sun
- Department of Nuclear Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
| | - Lingzhou Zhao
- Department of Nuclear Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
- Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Shanghai, 201620, China
| | - Jingchao Li
- State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Biological Science and Medical Engineering, Donghua University, Shanghai, 201620, China
| | - Yan Xing
- Department of Nuclear Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
| | - Jinhua Zhao
- Department of Nuclear Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
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41
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Gilgenkrantz H, Paradis V, Lotersztajn S. Cell metabolism-based therapy for liver fibrosis, repair, and hepatocellular carcinoma. Hepatology 2025; 81:269-287. [PMID: 37212145 PMCID: PMC11643143 DOI: 10.1097/hep.0000000000000479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Accepted: 04/21/2023] [Indexed: 05/23/2023]
Abstract
Progression of chronic liver injury to fibrosis, abnormal liver regeneration, and HCC is driven by a dysregulated dialog between epithelial cells and their microenvironment, in particular immune, fibroblasts, and endothelial cells. There is currently no antifibrogenic therapy, and drug treatment of HCC is limited to tyrosine kinase inhibitors and immunotherapy targeting the tumor microenvironment. Metabolic reprogramming of epithelial and nonparenchymal cells is critical at each stage of disease progression, suggesting that targeting specific metabolic pathways could constitute an interesting therapeutic approach. In this review, we discuss how modulating intrinsic metabolism of key effector liver cells might disrupt the pathogenic sequence from chronic liver injury to fibrosis/cirrhosis, regeneration, and HCC.
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Affiliation(s)
- Hélène Gilgenkrantz
- Paris-Cité University, INSERM, Center for Research on Inflammation, Paris, France
| | - Valérie Paradis
- Paris-Cité University, INSERM, Center for Research on Inflammation, Paris, France
- Pathology Department, Beaujon Hospital APHP, Paris-Cité University, Clichy, France
| | - Sophie Lotersztajn
- Paris-Cité University, INSERM, Center for Research on Inflammation, Paris, France
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42
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Shin E, Kim HM, Koo JS. CD68 positive and/or CD163 positive tumor-associated macrophages and PD-L1 expression in breast phyllodes tumor. Breast Cancer Res Treat 2025; 209:261-273. [PMID: 39242456 DOI: 10.1007/s10549-024-07487-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Accepted: 08/28/2024] [Indexed: 09/09/2024]
Abstract
INTRODUCTION PD-L1 expression and tumor-associated macrophage (TAM) status in phyllodes tumors (PT) have only been examined in a limited number of studies. This study aimed to investigate the expression of PD-L1 and TAM in breast PT and examine their implications. METHODS Tissue microarrays were constructed from 181 PT samples, and immunohistochemistry for PD-L1 antibodies (SP142, SP263, and 22C3) and TAM markers (CD68 and CD163) were performed. The staining results were compared and analyzed with clinicopathological parameters. RESULTS Of the 181 samples, 149 were benign, 27 were borderline, and five were malignant. The number of CD68- and/or CD163-positive TAMs increased with increasing PT grades (P < 0.001), and the number of CD68-positive TAMs was significantly positively correlated with that of CD163-positive TAMs (R = 0.704, P < 0.001). Some of the CD68- and/or CD163-positive cells exhibited positivity for actin staining, displaying hybrid characteristics that resemble both histiocytes and myofibroblasts. PD-L1 SP263 tumor cells and PD-L1 SP263 immune cells were the most expressed in malignant PTs (P < 0.001). The number of CD68- and/or CD163-positive TAMs increased when PD-L1 SP263 immune cells were expressed (P < 0.001). The number of CD68- and/or CD163-positive TAMs was positively correlated with PD-L1 22C3 immune cells (R = 0.299, P < 0.001 and R = 0.336, P < 0.001, respectively). Univariate analysis showed that PD-L1 SP263 immune cell expression (P = 0.016) was associated with shorter disease-free survival and that PD-L1 22C3 tumor cell expression (P < 0.001) was associated with shorter overall survival. CONCLUSION The number of CD68- and/or CD163-positive cells increases with increasing PT histological grade, and these cells exhibit hybrid characteristics, resembling both histiocyte and myofibroblasts.
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Affiliation(s)
- Eunah Shin
- Department of Pathology, Yonsei University College of Medicine, Seoul, South Korea
| | - Hye Min Kim
- Department of Pathology, Yonsei University College of Medicine, Seoul, South Korea
| | - Ja Seung Koo
- Department of Pathology, Yonsei University College of Medicine, Seoul, South Korea.
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Mo H, Zhang X, Ren L. Analysis of neuroglia and immune cells in the tumor microenvironment of breast cancer brain metastasis. Cancer Biol Ther 2024; 25:2398285. [PMID: 39238191 PMCID: PMC11382727 DOI: 10.1080/15384047.2024.2398285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Revised: 08/15/2024] [Accepted: 08/26/2024] [Indexed: 09/07/2024] Open
Abstract
Breast cancer stands as the most prevalent cancer diagnosed worldwide, often leading to brain metastasis, a challenging complication characterized by high mortality rates and a grim prognosis. Understanding the intricate mechanisms governing breast cancer brain metastasis (BCBM) remains an ongoing challenge. The unique microenvironment in the brain fosters an ideal setting for the colonization of breast cancer cells. The tumor microenvironment (TME) in brain metastases plays a pivotal role in the initiation and progression of BCBM, shaping the landscape for targeted therapeutic interventions. Current research primarily concentrates on unraveling the complexities of the TME in BCBM, with a particular emphasis on neuroglia and immune cells, such as microglia, monocyte-derived macrophages (MDMs), astrocytes and T cells. This comprehensive review delves deeply into these elements within the TME of BCBM, shedding light on their interplay, mechanisms, and potential as therapeutic targets to combat BCBM.
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Affiliation(s)
- Haixin Mo
- Clinical Experimental Center, Jiangmen Engineering Technology Research Center of Clinical Biobank and Translational Research, Jiangmen Central Hospital, Jiangmen, China
| | - Xin Zhang
- Clinical Experimental Center, Jiangmen Engineering Technology Research Center of Clinical Biobank and Translational Research, Jiangmen Central Hospital, Jiangmen, China
- Dongguan Key Laboratory of Medical Bioactive Molecular Developmental and Translational Research, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, China
- Collaborative Innovation Center for Antitumor Active Substance Research and Development, Guangdong Medical University, Zhanjiang, Guangdong, China
| | - Liangliang Ren
- Clinical Experimental Center, Jiangmen Engineering Technology Research Center of Clinical Biobank and Translational Research, Jiangmen Central Hospital, Jiangmen, China
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Guo J, Yang L, Song H, Bai L. Prevention of bleomycin-induced pulmonary fibrosis by vaccination with the Tocilizumab mimotope. Hum Vaccin Immunother 2024; 20:2319965. [PMID: 38408907 PMCID: PMC10900270 DOI: 10.1080/21645515.2024.2319965] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Accepted: 02/14/2024] [Indexed: 02/28/2024] Open
Abstract
Mimotope, a kind of peptide vaccine, is developed to bind natural receptor and inhibit the downstream signaling. We have demonstrated that the vaccination of Tocilizumab mimotopes could alleviate the renal fibrosis by interfering with both IL-6 and ferroptosis signaling. However, the effect of the vaccination of Tocilizumab mimotopes on the fibroblast was not investigated in previous study. Thus, we sought to explore the changes in the fibroblast induced by the Tocilizumab mimotopes vaccination. Bleomycin instillation was performed to construct the pulmonary fibrosis model after the immunization of Tocilizumab mimotopes. Lung histological analysis showed that the Tocilizumab mimotopes could significantly reduce the maladaptive repairment and abnormal remodeling. Immunoblotting assay and fluorescence staining showed that Immunization with the Tocilizumab mimotopes reduces the accumulation of fibrosis-related proteins. High level of lipid peroxidation product was observed in the animal model, while the Tocilizumab mimotopes vaccination could reduce the generation of lipid peroxidation product. Mechanism analysis further showed that Nrf-2 signaling, but not GPX-4 and FSP-1 signaling, was upregulated, and reduced the lipid peroxidation. Our results revealed that in the BLM-induced pulmonary fibrosis, high level of lipid peroxidation product was significantly accumulation in the lung tissues, which might lead to the occurrence of ferroptosis. The IL-6 pathway block therapy could inhibit lipid peroxidation product generation in the lung tissues by upregulating the Nrf-2 signaling, and further alleviate the pulmonary fibrosis.
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Affiliation(s)
- Jin Guo
- Department of Cardiorespiratory Rehabilitation, Shanghai Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), School of Medicine, Tongji University, Shanghai, China
| | - Lin Yang
- Department of Nephrology, Shanghai Fifth People’s Hospital, Fudan University, Shanghai, China
| | - Haoming Song
- Department of Cardiology, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Li Bai
- The Central Lab, The First Affiliated Hospital of Baotou Medical College (Inner Mongolia Autoimmune Key Laboratory), Baotou, China
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45
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Xiao LX, Li XJ, Yu HY, Qiu RJ, Zhai ZY, Ding WF, Zhu MS, Zhong W, Fang CF, Yang J, Chen T, Yu J. Macrophage-derived cathepsin L promotes epithelial-mesenchymal transition and M2 polarization in gastric cancer. World J Gastroenterol 2024; 30:5032-5054. [PMID: 39713169 PMCID: PMC11612860 DOI: 10.3748/wjg.v30.i47.5032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Revised: 09/11/2024] [Accepted: 10/13/2024] [Indexed: 11/26/2024] Open
Abstract
BACKGROUND Advanced gastric tumors are extremely prone to metastasize the in 20%-30% of gastric cancer, and patients have a poor prognosis despite systemic chemotherapy. Peritoneal metastases from gastric cancer usually indicate the end stage of the disease without curative treatment. AIM To peritoneal metastasis for facilitating clinical therapy are urgently needed. METHODS Immunohistochemical staining and immunofluorescence staining were used to demonstrate the high expression of cathepsin L (CTSL) in human gastric cancer tissues and its localization in cells. Lentivirus transfection was used to construct stable cell lines. Transwell invasion assays, wound healing assays, and animal tests were used to determine the relationships between CTSL and epithelial-mesenchymal transition (EMT) and tumorigenic potential in vivo. RESULTS We observed that macrophage-derived CTSL promoted gastric cancer cell migration and metastasis via the EMT pathway in vitro and in vivo, which involved macrophage polarization. Our findings suggest that macrophages improve extracellular matrix remodeling and hence facilitate tumor metastasis. Ablation of CTSL in macrophages within the tumor microenvironment may improve tumor therapy and the prognosis of patients with gastric cancer peritoneal metastasis. CONCLUSION In consideration of our findings, tumor-associated macrophage-derived CTSL is an important factor that promotes the metastasis and invasion of gastric cancer cells, and the targeting of CTSL may potentially improve the prognosis of patients with gastric cancer with peritoneal metastasis.
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Affiliation(s)
- Lu-Xi Xiao
- Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Xun-Jun Li
- Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Hai-Yi Yu
- Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Ren-Jie Qiu
- Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Zhong-Ya Zhai
- Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Wen-Fu Ding
- Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Man-Sheng Zhu
- Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Wu Zhong
- Department of Gastrointestinal and Hernia Surgery, Ganzhou Hospital-Nanfang Hospital, Ganzhou 341099, Jiangxi Province, China
| | - Chuan-Fa Fang
- Department of Gastrointestinal and Hernia Surgery, Ganzhou Hospital-Nanfang Hospital, Ganzhou 341099, Jiangxi Province, China
| | - Jia Yang
- Department of Gastrointestinal Surgery, Central Hospital of Wuhan, Wuhan 430014, Hubei Province, China
- Department of General Surgery, Xiangyang Central Hospital, The Affiliated Hospital of Hubei University of Arts and Science, Xiangyang 441021, Hubei Province, China
| | - Tao Chen
- Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
- Department of Gastrointestinal and Hernia Surgery, Ganzhou Hospital-Nanfang Hospital, Ganzhou 341099, Jiangxi Province, China
| | - Jiang Yu
- Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
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Duan H, He Z, Chen Z, Chen Y, Hu W, Sai K, Zhang X, Xia J, Li Y, Liu R, Zou C, Chen Z, Mou Y. Long-term survival after local immunotherapy for malignant gliomas: a retrospective study with 20 years follow-up. BMC Immunol 2024; 25:83. [PMID: 39707189 DOI: 10.1186/s12865-024-00676-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Accepted: 12/03/2024] [Indexed: 12/23/2024] Open
Abstract
PURPOSE Immunotherapy is a promising treatment for cancers but should be optimized for malignant gliomas. Because of immune privilege feature of the brain, local administration of immunotherapy may be a promising strategy for malignant glioma treatment. Identification of patients who may benefit from local immunotherapy is essential. METHODS We retrospectively reviewed the clinicopathological characteristics and outcomes of six malignant glioma patients who received local administration of autologous cytokine-induced killer (CIK) cells through Ommaya reservoirs implanted into the tumor resection cavity. Profiles of tumor genome, transcriptome and immune microenvironment were also investigated by genomic target sequencing, RNA sequencing, electrochemiluminescence assay and immunohistochemistry (IHC) staining. RESULTS Four patients died from tumor progression and the overall survival ranged from 10.0 to 33.9 months. Remarkably, two patients, including one diagnosed as diffuse hemispheric glioma H3 G34-mutant (G34-DHG, WHO grade 4) and the other diagnosed as astrocytoma (IDH1 mutation, WHO grade 3) survived more than 20 years without evidence of recurrence. The distinctive clinical feature of the two long-term survivors was tumor gross total resection (GTR) before CIK therapy. NTRK1 mutation was uniquely present and 353 genes were differentially expressed in the long-term survivors compared with the short-term survivors. These differential expression genes were highly associated with immune function. Electrochemiluminescence assay and IHC staining revealed higher expressions of cytokines and lower infiltrations of tumor-associated macrophages in the tumors of the long-term survivors. CONCLUSION These findings suggest that certain patients diagnosed as malignant gliomas, including G34-DHG (WHO grade 4), can acquire long-term survival after local immunotherapy. Tumor GTR before local immunotherapy and relatively weaker immunosuppressive tumor microenvironment are the favorable factors for long-term survival. Larger, controlled studies with standardized treatment protocols, including consistent use of GTR, are warranted to further evaluate the potential benefits of locally delivered immunotherapy.
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Affiliation(s)
- Hao Duan
- Department of Neurosurgery/Neuro-Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People's Republic of China
| | - Zhenqiang He
- Department of Neurosurgery/Neuro-Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People's Republic of China
| | - Zhenghe Chen
- Department of Neurosurgery/Neuro-Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People's Republic of China
| | - Yukun Chen
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People's Republic of China
| | - Wanming Hu
- Department of Pathology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People's Republic of China
| | - Ke Sai
- Department of Neurosurgery/Neuro-Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People's Republic of China
| | - Xiangheng Zhang
- Department of Neurosurgery/Neuro-Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People's Republic of China
| | - Jianchuan Xia
- Department of Biotherapy, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People's Republic of China
| | - Yongqiang Li
- Department of Biotherapy, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People's Republic of China
| | - Ranyi Liu
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People's Republic of China
| | - Chaowei Zou
- Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, People's Republic of China
| | - Zhongping Chen
- Department of Neurosurgery/Neuro-Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People's Republic of China
| | - Yonggao Mou
- Department of Neurosurgery/Neuro-Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People's Republic of China.
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Shen H, Zuo F. Prognostic role of systemic inflammation response index (SIRI) in patients with pancreatic cancer: a meta-analysis. Front Oncol 2024; 14:1465279. [PMID: 39723376 PMCID: PMC11668680 DOI: 10.3389/fonc.2024.1465279] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Accepted: 11/26/2024] [Indexed: 12/28/2024] Open
Abstract
Background The significance of the systemic inflammation response index (SIRI) in predicting the prognosis of patients with pancreatic cancer (PC) has been extensively explored; however, findings remain controversial. As such, this meta-analysis was performed to more precisely determine the utility of the SIRI in predicting PC prognosis. Methods A comprehensive literature search of the PubMed, Web of Science, Embase, and Cochrane Library databases for relevant studies, published up to June 25, 2024, was performed. The primary and secondary endpoints were overall survival (OS) and progression-free survival (PFS), respectively. The prognostic utility of the SIRI in predicting PC prognosis was estimated by calculating pooled hazard ratios (HRs) and corresponding 95% confidence intervals (CIs). Results Seven studies comprising 1160 patients were included in the present meta-analysis. Pooled findings revealed that elevated SIRI was as a prominent prognostic marker of OS (HR 2.40 [95% CI 1.88-3.05]; p<0.001) and PFS (HR 1.95 [95% CI 1.19-3.21]; p=0.008) in patients diagnosed with PC. According to subgroup analysis, the SIRI remained an outstanding prognostic marker for OS, irrespective of region, sample size, study center, study design, TNM stage, cancer type, cut-off value, treatment, or survival analysis type (all p<0.05). Moreover, based on subgroup analysis, the SIRI demonstrated significant utility in predicting PFS, irrespective of region and threshold value (p<0.05). Conclusion Results of the present meta-analysis revealed that an increased SIRI significantly predicted OS and PFS in patients diagnosed with PC. Considering its cost-effectiveness and availability, the SIRI may be a promising biomarker for predicting prognosis in patients with PC.
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Affiliation(s)
- Huifen Shen
- Department of Neurology, Huzhou Central Hospital, Affiliated Central Hospital of Huzhou University, Huzhou, Zhejiang, China
| | - Fei Zuo
- Department of Gastroenterology, Huzhou Central Hospital, Affiliated Central Hospital of Huzhou University, Huzhou, Zhejiang, China
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Bannister ME, Chatterjee DA, Shetty S, Patten DA. The Role of Macrophages in Hepatocellular Carcinoma and Their Therapeutic Potential. Int J Mol Sci 2024; 25:13167. [PMID: 39684877 DOI: 10.3390/ijms252313167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Revised: 12/05/2024] [Accepted: 12/06/2024] [Indexed: 12/18/2024] Open
Abstract
Hepatocellular carcinoma (HCC) represents a significant clinical burden globally and is predicted to continue to increase in incidence for the foreseeable future. The treatment of HCC is complicated by the fact that, in the majority of cases, it develops on a background of advanced chronic inflammatory liver disease. Chronic inflammation can foster an immunosuppressive microenvironment that promotes tumour progression and metastasis. In this setting, macrophages make up a major immune component of the HCC tumour microenvironment, and in this review, we focus on their contribution to HCC development and progression. Tumour-associated macrophages (TAMs) are largely derived from infiltrating monocytes and their potent anti-inflammatory phenotype can be induced by factors that are found within the tumour microenvironment, such as growth factors, cytokines, hypoxia, and extracellular matrix (ECM) proteins. In general, experimental evidence suggest that TAMs can exhibit a variety of functions that aid HCC tumour progression, including the promotion of angiogenesis, resistance to drug therapy, and releasing factors that support tumour cell proliferation and metastasis. Despite their tumour-promoting profile, there is evidence that the underlying plasticity of these cells can be targeted to help reprogramme TAMs to drive tumour-specific immune responses. We discuss the potential for targeting TAMs therapeutically either by altering their phenotype within the HCC microenvironment or by cell therapy approaches by taking advantage of their infiltrative properties from the circulation into tumour tissue.
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Affiliation(s)
- Megan E Bannister
- Centre for Liver and Gastrointestinal Research, School of Infection, Inflammation and Immunology, University of Birmingham, Birmingham B15 2TT, UK
| | - Devnandan A Chatterjee
- Centre for Liver and Gastrointestinal Research, School of Infection, Inflammation and Immunology, University of Birmingham, Birmingham B15 2TT, UK
- National Institute for Health Research, Birmingham Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust, Birmingham B15 2TH, UK
| | - Shishir Shetty
- Centre for Liver and Gastrointestinal Research, School of Infection, Inflammation and Immunology, University of Birmingham, Birmingham B15 2TT, UK
- National Institute for Health Research, Birmingham Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust, Birmingham B15 2TH, UK
| | - Daniel A Patten
- Centre for Liver and Gastrointestinal Research, School of Infection, Inflammation and Immunology, University of Birmingham, Birmingham B15 2TT, UK
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Jing S, Zhao L, Zhao L, Gao Y, He T. TRIP13: A promising cancer immunotherapy target. CANCER INNOVATION 2024; 3:e147. [PMID: 39398261 PMCID: PMC11467489 DOI: 10.1002/cai2.147] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Revised: 03/21/2024] [Accepted: 05/12/2024] [Indexed: 10/15/2024]
Abstract
The tumor microenvironment (TME) facilitates tumor development through intricate intercellular signaling, thereby supporting tumor growth and suppressing the immune response. Thyroid hormone receptor interactor 13 (TRIP13), an AAA+ ATPase, modulates the conformation of client macromolecules, consequently influencing cellular signaling pathways. TRIP13 has been implicated in processes such as proliferation, invasion, migration, and metastasis during tumor progression. Recent studies have revealed that TRIP13 also plays a role in immune response suppression within the TME. Thus, inhibiting these functions of TRIP13 could potentially enhance immune responses and improve the efficacy of immune checkpoint inhibition. This review summarizes the recent research progress of TRIP13 and discusses the potential of targeting TRIP13 to improve immune-based therapies for patients with cancer.
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Affiliation(s)
- Shengnan Jing
- Institute of Pain Medicine and Special Environmental Medicine, Co‐innovation Center of NeuroregenerationNantong UniversityNantongJiangsuChina
| | - Liya Zhao
- Institute of Pain Medicine and Special Environmental Medicine, Co‐innovation Center of NeuroregenerationNantong UniversityNantongJiangsuChina
| | - Liwen Zhao
- Institute of Pain Medicine and Special Environmental Medicine, Co‐innovation Center of NeuroregenerationNantong UniversityNantongJiangsuChina
| | - Yong‐Jing Gao
- Institute of Pain Medicine and Special Environmental Medicine, Co‐innovation Center of NeuroregenerationNantong UniversityNantongJiangsuChina
| | - Tianzhen He
- Institute of Pain Medicine and Special Environmental Medicine, Co‐innovation Center of NeuroregenerationNantong UniversityNantongJiangsuChina
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Mohamed MM, Schneider RJ. Multifunctional role of the tumor-associated monocytes/macrophages in the metastatic potential of inflammatory breast cancer. QJM 2024; 117:831-835. [PMID: 39437012 DOI: 10.1093/qjmed/hcae195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Revised: 09/13/2024] [Indexed: 10/25/2024] Open
Abstract
Inflammatory breast cancer (IBC) is the most aggressive and lethal phenotype form of breast cancer, which afflicts young women at high incidence in North Africa compared to other continents of the world. IBC is characterized by highly metastatic behavior and possesses specific pathobiological properties different from non-IBC. IBC disease displays unusual common properties at typical presentation, including positive metastatic lymph nodes, high infiltration of tumor-associated monocytes/macrophages (TAMs/Ms), rapid progression to distant metastasis and possibly the production of a unique repertoire of growth factors, cytokines and chemokines, as well as a striking association with different polarized macrophages compared to non-IBC. Indeed, TAMs/Ms play a crucial role in breast cancer development. Previously, we showed that cross-talk between IBC cells and patient-derived TAMs occurs via secretion of inflammatory mediators from TAMs that act on specific extracellular domain receptors activating down-stream signaling pathways that promote the epithelial-to-mesenchymal transition, cancer cell invasion, IBC stem cell properties, drug resistance, local and metastatic recurrence of residual tumor cells and other key markers of malignancy, including in vitro colony formation capacity. In this mini-review, we will discuss the role of TAMs in IBC cancer metastatic potential and molecules involved. The review also discusses the recent discoveries in the field of IBC research.
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Affiliation(s)
| | - Robert J Schneider
- Department of Microbiology, NYU Grossman School of Medicine, New York, NY, USA
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