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Karim M, Hasan MM, Kim SH, Azam Z, Wahab R, Islam T, Alam F, Kim YJ, Bae DJ, Roy S, Grippo P, Bishehsari F, Choi JU, Al-Hilal TA. Stromal fibrin shapes immune infiltration landscape of pancreatic ductal adenocarcinoma. Biomaterials 2025; 320:123280. [PMID: 40147113 DOI: 10.1016/j.biomaterials.2025.123280] [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: 10/28/2024] [Revised: 03/18/2025] [Accepted: 03/20/2025] [Indexed: 03/29/2025]
Abstract
In pancreatic ductal adenocarcinoma (PDAC), in-situ coagulation creates a thrombotic, crosslinked fibrin (x-fibrin)-rich tumor stroma (FibTS), whose impact on immune cell behavior remains unclear. We aimed to elucidate how FibTS in PDAC regulates immune cell infiltration, polarization, and crosstalk that favors immunosuppressive microenvironment and tumor growth. We assessed the spatial distribution of immune cells by multiplex immunostaining of human PDAC tissues, along with novel bioengineering and mouse tumor models. We investigated how FibTS influences the infiltration of tumor-associated macrophage (TAM) and T-cell subtypes and identified two distinct variants of PDAC, fibrin-high (Fibhi) and fibrin-low (Fiblow). Our findings reveal that PDAC cells secrete fibrinogen and thrombin to form FibTS, which acts as a physical barrier and biochemical niche that restricts CD8+ T-cell and TAM penetration into the tumor. The FibTS impeded immune cell penetration from the tumor stroma into the tumor parenchyma. Selective inhibition of FibTS formation by genetic and pharmacological tools altered the infiltration patterns of CD8+ T-cells and TAMs, decelerating PDAC growth. This study demonstrates that the barrier function of FibTS is crucial for immune evasion, particularly against macrophage and T-cell activity, presenting a potential therapeutic strategy to reshape the immune landscape within PDAC and slow tumor progression.
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Affiliation(s)
- Mazharul Karim
- Department of Molecular Pharmaceutics, University of Utah, Salt Lake City, UT, USA; Department of Pharmaceutical Sciences, School of Pharmacy, University of Texas at El Paso, El Paso, TX 79968, USA
| | - Md Mahedi Hasan
- Department of Biomedical Engineering, University of Utah, Salt Lake City, UT, USA
| | - Seung Hyun Kim
- College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea, 02453
| | - Zulfikar Azam
- Department of Molecular Pharmaceutics, University of Utah, Salt Lake City, UT, USA
| | - Riajul Wahab
- Department of Molecular Pharmaceutics, University of Utah, Salt Lake City, UT, USA
| | - Tamanna Islam
- Department of Biomedical Engineering, University of Utah, Salt Lake City, UT, USA
| | - Farzana Alam
- Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT, USA
| | - Yun-Jae Kim
- PrismCDX, Hwaseong-si, Gyeonggi-do, Republic of Korea
| | - Dong-Jun Bae
- PrismCDX, Hwaseong-si, Gyeonggi-do, Republic of Korea
| | - Sourav Roy
- Department of Biological Sciences, College of Sciences, University of Texas at El Paso, El Paso, TX, 79968, USA
| | - Paul Grippo
- Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA
| | - Faraz Bishehsari
- Gastroenterology Research Center, Division of Gastroenterology, Hepatology & Nutrition, Department of Internal Medicine, University of Texas Houston, TX 77030, USA; MD Anderson Cancer Center-UTHealth Houston Graduate School of Biomedical Sciences, USA
| | - Jeong Uk Choi
- College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea, 02453.
| | - Taslim A Al-Hilal
- Department of Molecular Pharmaceutics, University of Utah, Salt Lake City, UT, USA; Department of Biomedical Engineering, University of Utah, Salt Lake City, UT, USA.
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Deipenbrock A, Wilmes BE, Sommermann T, Abdo N, Moustakas K, Raasch M, Rennert K, Teusch NE. Modelling of the multicellular tumor microenvironment of pancreatic ductal adenocarcinoma (PDAC) on a fit-for-purpose biochip for preclinical drug discovery. LAB ON A CHIP 2025; 25:2168-2181. [PMID: 40018951 DOI: 10.1039/d4lc01016g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/01/2025]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most common and lethal form of pancreatic cancer. One major cause for a fast disease progression is the presence of a highly fibrotic tumor microenvironment (TME) mainly composed of cancer-associated fibroblasts (CAF), and various immune cells, especially tumor-associated macrophages (TAM). To conclusively evaluate drug efficacy, it is crucial to develop in vitro models that can recapitulate the cross talk between tumor cells and the surrounding stroma. Here, we constructed a fit-for-purpose biochip platform which allows the integration of PDAC spheroids (composed of PANC-1 cells and pancreatic stellate cells (PSC)). Additionally, the chip design enables dynamic administration of drugs or immune cells via a layer of human umbilical vein endothelial cells (HUVEC). As a proof-of-concept for drug administration, vorinostat, an FDA-approved histone deacetylase inhibitor for cutaneous T cell lymphoma (CTCL), subjected via continuous flow for 72 h, resulted in a significantly reduced viability of PDAC spheroids without affecting vascular integrity. Furthermore, dynamic perfusion with peripheral mononuclear blood cells (PBMC)-derived monocytes resulted in an immune cell migration through the endothelium into the spheroids. After 72 h of infiltration, monocytes differentiated into macrophages which polarized into the M2 phenotype. The polarization into M2 macrophages persisted for at least 168 h, verified by expression of the M2 marker CD163 which increased from 72 h to 168 h, while the M1 markers CD86 and HLA-DR were significantly downregulated. Overall, the described spheroid-on-chip model allows the evaluation of novel therapeutic strategies by mimicking and targeting the complex TME of PDAC.
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Affiliation(s)
- Alina Deipenbrock
- Institute of Pharmaceutical Biology and Biotechnology, Heinrich-Heine-University Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany.
| | - Ben Eric Wilmes
- Institute of Pharmaceutical Biology and Biotechnology, Heinrich-Heine-University Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany.
| | | | | | - Kyra Moustakas
- Institute of Pharmaceutical Biology and Biotechnology, Heinrich-Heine-University Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany.
| | | | | | - Nicole E Teusch
- Institute of Pharmaceutical Biology and Biotechnology, Heinrich-Heine-University Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany.
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Ni P, Li L, Du K, Nov P, Wang D, Wang C, Kou Q, Li Y, Zhang Y, Zheng C, Fu W, Li J. Unveiling the immunological terrain of pancreatic ductal adenocarcinoma: strategies to prompt immunotherapy from Mendelian randomization. Discov Oncol 2025; 16:613. [PMID: 40279021 PMCID: PMC12031697 DOI: 10.1007/s12672-025-02250-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Accepted: 03/27/2025] [Indexed: 04/26/2025] Open
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is challenging to treat due to its immunosuppressive tumor microenvironment (TME) and resistance to immune checkpoint inhibitors. This study aims to discover new therapeutic targets and predictive biomarkers for PDAC. METHODS Using Mendelian randomization, we studied causal relationships between PDAC and an array of immune cell traits, bacterial traits, inflammatory factors, and blood metabolites. We employed large genome-wide association study datasets and the two-sample MR approach for the investigation. RESULTS Our results highlight suggestive evidence of associations between PDAC and distinct immune cell phenotypes, revealing nuanced alterations across monocytes, T-cells, B-cells, dendritic cells, and myeloid-derived suppressor cells. Our study provides a granular view of the PDAC-immune interface, identifying key immune cell traits and their associations with PDAC. For instance, our findings suggest a detrimental reduction in various monocyte traits, alongside a decrease in B-cell populations. Conversely, certain T-cell subsets showed increased associations, indicating potential targets for immunotherapeutic strategies. The bacterial trait associations, particularly with Collinsella and Ruminococcus torques, highlight the gut microbiome's influence on immune modulation and PDAC pathogenesis. Additionally, the traits concerning Interleukin-12 subunit beta levels and T-cell surface glycoprotein CD5 levels further indicate their function of this complex interaction. CONCLUSIONS This study enhances our understanding of PDAC's resistance to immunotherapies and highlights the potential of personalized immunotherapy and metabolic pathway modulation in PDAC treatment. Our findings provide supportive evidence for research and clinical translation.
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Affiliation(s)
- Peizan Ni
- Department of Radiotherapy, Oncology Center, Zhujiang Hospital, Southern Medical University, No. 253, Industrial Avenue, Guangzhou, 510280, Guangdong, China
| | - Lilin Li
- Department of Radiotherapy, Oncology Center, Zhujiang Hospital, Southern Medical University, No. 253, Industrial Avenue, Guangzhou, 510280, Guangdong, China
| | - KunPeng Du
- Department of Radiotherapy, Oncology Center, Zhujiang Hospital, Southern Medical University, No. 253, Industrial Avenue, Guangzhou, 510280, Guangdong, China
| | - Pengkhun Nov
- Department of Radiotherapy, Oncology Center, Zhujiang Hospital, Southern Medical University, No. 253, Industrial Avenue, Guangzhou, 510280, Guangdong, China
| | - Duanyu Wang
- Department of Radiotherapy, Oncology Center, Zhujiang Hospital, Southern Medical University, No. 253, Industrial Avenue, Guangzhou, 510280, Guangdong, China
| | - Changqian Wang
- Department of Radiotherapy, Oncology Center, Zhujiang Hospital, Southern Medical University, No. 253, Industrial Avenue, Guangzhou, 510280, Guangdong, China
| | - Qianzi Kou
- Department of Radiotherapy, Oncology Center, Zhujiang Hospital, Southern Medical University, No. 253, Industrial Avenue, Guangzhou, 510280, Guangdong, China
| | - Ying Li
- Department of Radiotherapy, Oncology Center, Zhujiang Hospital, Southern Medical University, No. 253, Industrial Avenue, Guangzhou, 510280, Guangdong, China
| | - Yangfeng Zhang
- Department of Radiotherapy, Oncology Center, Zhujiang Hospital, Southern Medical University, No. 253, Industrial Avenue, Guangzhou, 510280, Guangdong, China
| | - Chongyang Zheng
- Department of Radiotherapy, Oncology Center, Zhujiang Hospital, Southern Medical University, No. 253, Industrial Avenue, Guangzhou, 510280, Guangdong, China
| | - Wen Fu
- Department of Radiotherapy, Oncology Center, Zhujiang Hospital, Southern Medical University, No. 253, Industrial Avenue, Guangzhou, 510280, Guangdong, China
| | - Jiqiang Li
- Department of Radiotherapy, Oncology Center, Zhujiang Hospital, Southern Medical University, No. 253, Industrial Avenue, Guangzhou, 510280, Guangdong, China.
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Toghraie FS, Bayat M, Hosseini MS, Ramezani A. Tumor-infiltrating myeloid cells; mechanisms, functional significance, and targeting in cancer therapy. Cell Oncol (Dordr) 2025:10.1007/s13402-025-01051-y. [PMID: 39998754 DOI: 10.1007/s13402-025-01051-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/20/2025] [Indexed: 02/27/2025] Open
Abstract
Tumor-infiltrating myeloid cells (TIMs), which encompass tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), myeloid-derived suppressor cells (MDSCs), and tumor-associated dendritic cells (TADCs), are of great importance in tumor microenvironment (TME) and are integral to both pro- and anti-tumor immunity. Nevertheless, the phenotypic heterogeneity and functional plasticity of TIMs have posed challenges in fully understanding their complexity roles within the TME. Emerging evidence suggested that the presence of TIMs is frequently linked to prevention of cancer treatment and improvement of patient outcomes and survival. Given their pivotal function in the TME, TIMs have recently been recognized as critical targets for therapeutic approaches aimed at augmenting immunostimulatory myeloid cell populations while depleting or modifying those that are immunosuppressive. This review will explore the important properties of TIMs related to immunity, angiogenesis, and metastasis. We will also document the latest therapeutic strategies targeting TIMs in preclinical and clinical settings. Our objective is to illustrate the potential of TIMs as immunological targets that may improve the outcomes of existing cancer treatments.
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Affiliation(s)
- Fatemeh Sadat Toghraie
- Institute of Biotechnology, Faculty of the Environment and Natural Sciences, Brandenburg University of Technology, Cottbus, Germany
| | - Maryam Bayat
- Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mahsa Sadat Hosseini
- Regenerative Medicine Research Center, Isfahan University of Medical Sciences, Isfahan, Iran.
| | - Amin Ramezani
- Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
- Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran.
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5
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Thielman NRJ, Funes V, Davuluri S, Ibanez HE, Sun WC, Fu J, Li K, Muth S, Pan X, Fujiwara K, Thomas DL, Henderson M, Teh SS, Zhu Q, Thompson E, Jaffee EM, Kolodkin A, Meng F, Zheng L. Semaphorin 3D promotes pancreatic ductal adenocarcinoma progression and metastasis through macrophage reprogramming. SCIENCE ADVANCES 2024; 10:eadp0684. [PMID: 39413197 PMCID: PMC11801256 DOI: 10.1126/sciadv.adp0684] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Accepted: 09/11/2024] [Indexed: 10/18/2024]
Abstract
Axon guidance molecules are frequently altered in pancreatic ductal adenocarcinoma (PDA) and influence PDA progression. However, the molecular mechanism remained unclear. Using genetically engineered mouse models to examine semaphorin 3D (SEMA3D), we identified a dual role for tumor- and nerve-derived SEMA3D in the malignant transformation of pancreatic epithelial cells and invasive PDA development. Pancreatic-specific knockout of the SEMA3D gene from the KRASG12D and TP53R172H mutation knock-in, PDX1-Cre(KPC) mouse model demonstrated delayed tumor initiation, prolonged survival, absence of metastasis, and reduced M2 macrophage expression. Mechanistically, tumor- and nerve-derived SEMA3D indirectly reprograms macrophages through KRASMUT-dependent ARF6 signaling in PDA cells, resulting in increased lactate production, which is sensed by GPCR132 on macrophages to stimulate protumorigenic M2 polarization. Multiplex immunohistochemistry demonstrated increased M2-polarized macrophages proximal to nerves in SEMA3D-expressing human PDA tissue. This study suggests that altered SEMA3D expression leads to an acquisition of cancer-promoting functions, and nerve-derived SEMA3D is "hijacked" by PDA cells to support growth and metastasis in a KRASMUT-dependent manner.
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Affiliation(s)
- Noelle R. J. Thielman
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Lake Erie College of Osteopathic Medicine, Erie, PA 16509, USA
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Pancreatic Cancer Precision Medicine Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Vanessa Funes
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Pancreatic Cancer Precision Medicine Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Sanjana Davuluri
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Pancreatic Cancer Precision Medicine Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Department of Molecular Microbiology and Immunology, Johns Hopkins University School of Public Health, Baltimore, MD 21287, USA
| | - Hector E. Ibanez
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Pancreatic Cancer Precision Medicine Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Wei-Chih Sun
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Pancreatic Cancer Precision Medicine Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Juan Fu
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Pancreatic Cancer Precision Medicine Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Keyu Li
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Pancreatic Cancer Precision Medicine Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Division of Pancreatic Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Stephen Muth
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Pancreatic Cancer Precision Medicine Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Xingyi Pan
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Pancreatic Cancer Precision Medicine Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Kenji Fujiwara
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Pancreatic Cancer Precision Medicine Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Department of Surgery, Kimura Hospital and Department of Surgery; Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Dwayne L. Thomas
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Pancreatic Cancer Precision Medicine Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - MacKenzie Henderson
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Pancreatic Cancer Precision Medicine Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Selina Shiqing Teh
- Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Qingfeng Zhu
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Pancreatic Cancer Precision Medicine Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Elizabeth Thompson
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Pancreatic Cancer Precision Medicine Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Elizabeth M. Jaffee
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Pancreatic Cancer Precision Medicine Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
- Skip Viragh Center for Pancreatic Cancer, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Cancer Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
| | - Alex Kolodkin
- Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Department of Neuroscience, Kavli Neuroscience Discovery Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Fengxi Meng
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Shanghai Eye and ENT Hospital, Fudan University, Shanghai 200031, China
| | - Lei Zheng
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Pancreatic Cancer Precision Medicine Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
- Skip Viragh Center for Pancreatic Cancer, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
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Hashemzadeh MS, Esmaeili Gouvarchin Ghaleh H, Mohammadi M, Yousefpoor Y, Rezaei E, Alishiri G. Therapeutic Effects of IL-1RA, M2 Cells, and Their Synergistic Impact on a Mouse Model of Rheumatoid Arthritis. Adv Pharm Bull 2024; 14:483-495. [PMID: 39206397 PMCID: PMC11347727 DOI: 10.34172/apb.2024.037] [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: 08/05/2023] [Revised: 01/30/2024] [Accepted: 03/03/2024] [Indexed: 09/04/2024] Open
Abstract
Purpose Rheumatoid arthritis (RA) is a type of autoimmune disease that results in chronic inflammation of the joint synovial tissue, leading to joint damage and significant disability. Despite ongoing research, the exact cause of RA remains unclear, and current treatments have limitations. This study explores the potential of utilizing interleukin-1 receptor antagonist (IL-1RA) and anti-inflammatory macrophages polarized in the vicinity of the supernatant from allogeneic mesenchymal stem cells (MSCs) as a novel therapeutic approach for RA. Methods An expression cassette containing the IL-1RA gene was constructed and expressed in E. coli BL21. The resulting protein was purified and stabilized for use in in vivo experiments. Bone marrow MSCs were isolated and used to produce anti-inflammatory M2 macrophages from the isolated peripheral blood monocytes. The macrophages were then used to treat mice with RA induced by collagen type II. Results The combination of IL-1RA and M2 macrophages improved clinical and histopathological symptoms of the disease, reduced levels of inflammatory factors, and modulated the immune system in the treated mouse groups. The results showed that this combinatory therapy had a synergistic effect for RA treatment. Conclusion The simultaneous use of IL-1RA and M2 cells could be a promising approach for the treatment of RA. This combinatory therapy has the potential to improve the disease and decrease the severity of inflammation in patients with RA.
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Affiliation(s)
| | | | - Mozafar Mohammadi
- Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Yaser Yousefpoor
- Department of Medical Biotechnology, School of Paramedical Sciences, Torbat Heydariyeh University of Medical Sciences, Iran
| | - Ehsan Rezaei
- Molecular Biology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Gholamhossein Alishiri
- Chemical Injuries Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
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7
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Farhangnia P, Khorramdelazad H, Nickho H, Delbandi AA. Current and future immunotherapeutic approaches in pancreatic cancer treatment. J Hematol Oncol 2024; 17:40. [PMID: 38835055 PMCID: PMC11151541 DOI: 10.1186/s13045-024-01561-6] [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: 04/09/2024] [Accepted: 05/28/2024] [Indexed: 06/06/2024] Open
Abstract
Pancreatic cancer is a major cause of cancer-related death, but despondently, the outlook and prognosis for this resistant type of tumor have remained grim for a long time. Currently, it is extremely challenging to prevent or detect it early enough for effective treatment because patients rarely exhibit symptoms and there are no reliable indicators for detection. Most patients have advanced or spreading cancer that is difficult to treat, and treatments like chemotherapy and radiotherapy can only slightly prolong their life by a few months. Immunotherapy has revolutionized the treatment of pancreatic cancer, yet its effectiveness is limited by the tumor's immunosuppressive and hard-to-reach microenvironment. First, this article explains the immunosuppressive microenvironment of pancreatic cancer and highlights a wide range of immunotherapy options, including therapies involving oncolytic viruses, modified T cells (T-cell receptor [TCR]-engineered and chimeric antigen receptor [CAR] T-cell therapy), CAR natural killer cell therapy, cytokine-induced killer cells, immune checkpoint inhibitors, immunomodulators, cancer vaccines, and strategies targeting myeloid cells in the context of contemporary knowledge and future trends. Lastly, it discusses the main challenges ahead of pancreatic cancer immunotherapy.
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Affiliation(s)
- Pooya Farhangnia
- Reproductive Sciences and Technology Research Center, Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Immunology Board for Transplantation and Cell-Based Therapeutics (ImmunoTACT), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Hossein Khorramdelazad
- Department of Immunology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Hamid Nickho
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Ali-Akbar Delbandi
- Reproductive Sciences and Technology Research Center, Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran.
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
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8
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Li H, Wang S, Yang Z, Meng X, Niu M. Nanomaterials modulate tumor-associated macrophages for the treatment of digestive system tumors. Bioact Mater 2024; 36:376-412. [PMID: 38544737 PMCID: PMC10965438 DOI: 10.1016/j.bioactmat.2024.03.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Revised: 02/25/2024] [Accepted: 03/03/2024] [Indexed: 11/25/2024] Open
Abstract
The treatment of digestive system tumors presents challenges, particularly in immunotherapy, owing to the advanced immune tolerance of the digestive system. Nanomaterials have emerged as a promising approach for addressing these challenges. They provide targeted drug delivery, enhanced permeability, high bioavailability, and low toxicity. Additionally, nanomaterials target immunosuppressive cells and reshape the tumor immune microenvironment (TIME). Among the various cells in the TIME, tumor-associated macrophages (TAMs) are the most abundant and play a crucial role in tumor progression. Therefore, investigating the modulation of TAMs by nanomaterials for the treatment of digestive system tumors is of great significance. Here, we present a comprehensive review of the utilization of nanomaterials to modulate TAMs for the treatment of gastric cancer, colorectal cancer, hepatocellular carcinoma, and pancreatic cancer. We also investigated the underlying mechanisms by which nanomaterials modulate TAMs to treat tumors in the digestive system. Furthermore, this review summarizes the role of macrophage-derived nanomaterials in the treatment of digestive system tumors. Overall, this research offers valuable insights into the development of nanomaterials tailored for the treatment of digestive system tumors.
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Affiliation(s)
- Hao Li
- Department of Interventional Radiology, First Hospital of China Medical University, Shenyang, China
| | - Shuai Wang
- Department of Interventional Radiology, First Hospital of China Medical University, Shenyang, China
| | - Zhengqiang Yang
- Department of Interventional Therapy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xianwei Meng
- Laboratory of Controllable Preparation and Application of Nanomaterials, Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing, China
| | - Meng Niu
- China Medical University, Shenyang, China
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9
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Guo S, Wang Z. Unveiling the immunosuppressive landscape of pancreatic ductal adenocarcinoma: implications for innovative immunotherapy strategies. Front Oncol 2024; 14:1349308. [PMID: 38590651 PMCID: PMC10999533 DOI: 10.3389/fonc.2024.1349308] [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: 12/04/2023] [Accepted: 03/12/2024] [Indexed: 04/10/2024] Open
Abstract
Pancreatic cancer, particularly pancreatic ductal adenocarcinoma (PDAC), stands as the fourth leading cause of cancer-related deaths in the United States, marked by challenging treatment and dismal prognoses. As immunotherapy emerges as a promising avenue for mitigating PDAC's malignant progression, a comprehensive understanding of the tumor's immunosuppressive characteristics becomes imperative. This paper systematically delves into the intricate immunosuppressive network within PDAC, spotlighting the significant crosstalk between immunosuppressive cells and factors in the hypoxic acidic pancreatic tumor microenvironment. By elucidating these mechanisms, we aim to provide insights into potential immunotherapy strategies and treatment targets, laying the groundwork for future studies on PDAC immunosuppression. Recognizing the profound impact of immunosuppression on PDAC invasion and metastasis, this discussion aims to catalyze the development of more effective and targeted immunotherapies for PDAC patients.
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Affiliation(s)
- Songyu Guo
- First Clinical Medical College, Inner Mongolia Medical University, Hohhot, China
- Department of Hepatic-Biliary-Pancreatic Surgery, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot, China
| | - Zhenxia Wang
- Department of Hepatic-Biliary-Pancreatic Surgery, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot, China
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Tan S, Tang H, Zhang Z, Wang Y, Li H, Shi W, Ye H, Xie P, Zhou J. Identification of Transcriptomic Signatures of Pancreatic Ductal Adenocarcinoma-Derived Exosomes That Promote Macrophage M2 Polarization and Predict Prognosis: S100A9 Reveals Tumor Progression. Clin Med Insights Oncol 2024; 18:11795549241239042. [PMID: 38510315 PMCID: PMC10952989 DOI: 10.1177/11795549241239042] [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: 08/28/2023] [Accepted: 02/25/2024] [Indexed: 03/22/2024] Open
Abstract
Background Exosomes play a role in intercellular communication and participate in the interaction between pancreatic ductal adenocarcinoma (PDAC) cells and immune cells. Macrophages can receive tumor cell-derived exosomes to polarize into M2-type macrophages, which can enhance the invasion and metastasis of pancreatic cancer, leading to poor prognosis. However, the mechanism by which pancreatic cancer cell-derived exosomes promote M2-type macrophages is still unclear. Methods M2 macrophage-associated exosome-derived key module genes were identified by differentially expressed genes (DEGs) and weighted gene co-expression network analysis (WGCNA) analysis using exoRbase 2.0, The Cancer Genome Atlas (TCGA), and The International Cancer Genome Consortium (ICGC) databases. Multivariate Cox regression analysis was used to identify key prognostic genes and obtain regression coefficients to establish prognostic signature. Immune infiltration, tumor mutations, and GSEA among different risk groups were compared. exoRbase 2.0, Gene Expression Profiling Interactive Analysis 2 (GEPIA2), HPA, and TISCH2 databases were used to further analyze the expression pattern of S100A9 in pancreatic cancer. In vitro experiments, cell-derived exosome isolation, quantitative polymerase chain reaction (qPCR), western blot, flow cytometry analysis, cell transfection, transwell assay, and CCK-8 assay were applied to investigate the roles of S100A9 in macrophage M2 polarization and tumor progression. Results The key genes of PDAC-derived exosomes promoting M2-type macrophage polarization were identified, and a risk score model was established. The risk score is related to the expression of common immune checkpoints, immune score, and stromal score, and the tumor mutational burden and biological function of high- and low-risk groups were also different. S100A9 was positively correlated with M2-type macrophage marker. In addition, scRNA-seq data from the TISCH2 database revealed that S100A9 is predominantly expressed in pancreatic cancer cells and mono/macrophage cells, suggesting that S100A9 in pancreatic cancer cells could be received by macrophages, thereby inducing macrophage polarization. In vitro, we used exosomes from BxPC-3 cell lines to coculture macrophages and found that macrophages were mainly polarized toward M2 type, which further promoted the proliferation and metastasis of PDAC. Conclusions Our study established a reliable risk score model for PDAC-derived exosomes and M2 macrophages, identified the important role of S100A9 in macrophage M2 polarization, which provides a new strategy for the diagnosis and treatment of PDAC, and strengthened the understanding of the mechanism of tumor development and metastasis.
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Affiliation(s)
- Siyuan Tan
- Department of Surgery, School of Medicine, Southeast University, Nanjing, China
| | - Haodong Tang
- Department of Surgery, School of Medicine, Southeast University, Nanjing, China
| | - Zheng Zhang
- Department of Surgery, School of Medicine, Southeast University, Nanjing, China
| | - Yang Wang
- Department of Surgery, School of Medicine, Southeast University, Nanjing, China
- Department of Hepato-Pancreatico-Biliary Surgery, Zhongda Hospital Southeast University, Nanjing, China
| | - Haifeng Li
- Department of Surgery, School of Medicine, Southeast University, Nanjing, China
- Department of Hepato-Pancreatico-Biliary Surgery, Zhongda Hospital Southeast University, Nanjing, China
| | - Wenyuan Shi
- Department of Surgery, School of Medicine, Southeast University, Nanjing, China
| | - Hao Ye
- Department of Surgery, School of Medicine, Southeast University, Nanjing, China
| | - Peng Xie
- Department of Surgery, School of Medicine, Southeast University, Nanjing, China
- Department of Hepato-Pancreatico-Biliary Surgery, Zhongda Hospital Southeast University, Nanjing, China
| | - Jiahua Zhou
- Department of Surgery, School of Medicine, Southeast University, Nanjing, China
- Department of Hepato-Pancreatico-Biliary Surgery, Zhongda Hospital Southeast University, Nanjing, China
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Yamada Y, Yamamoto T, Tsutsumi C, Matsumoto T, Noguchi S, Shimada Y, Nakata K, Ohuchida K, Nakamura M, Oda Y. Immature stroma and high infiltration of CD15 + cells are predictive markers of poor prognosis in different subsets of patients with pancreatic cancer. Cancer Sci 2024; 115:1001-1013. [PMID: 38230840 PMCID: PMC10920995 DOI: 10.1111/cas.16060] [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: 09/06/2023] [Revised: 12/10/2023] [Accepted: 12/12/2023] [Indexed: 01/18/2024] Open
Abstract
Preoperative treatment is commonly carried out for borderline resectable pancreatic ductal adenocarcinoma (PDAC). However, the relationship between the combination of immune cells in the tumor microenvironment and their intratumoral heterogeneity along with their association with histological findings remains unclear, especially in patients receiving preoperative chemotherapy. We aimed to explore the therapeutic strategies for patients with PDAC with poor prognosis after receiving chemotherapy based on histological and immunological microenvironmental classifications. We investigated the correlation between the prognosis and histological immune microenvironmental factors of patients who initially underwent surgery (n = 100) and were receiving gemcitabine plus nab-paclitaxel (GEM + nabPTX) as preoperative chemotherapy (n = 103). Immune profiles were generated based on immune cell infiltration into the tumor, and their correlation with patient outcomes and histological features was analyzed. Tumor-infiltrating neutrophils (TINs) were identified as independent poor prognostic factors using multivariate analysis in both surgery-first and preoperative chemotherapy groups. The patients were further classified into four groups based on immune cell infiltration into the tumor. Patients with high CD15 infiltration into the tumor and immature stroma at the cancer margins showed the worst prognosis in the preoperative chemotherapy group. The analysis of mRNA expression and immunohistochemical features revealed that CXCR2, the receptor for CXCL8, was correlated with disease-free and overall survival. We inferred that patients with immature stroma at the margins and high infiltration of CD15+ neutrophils within the tumor showed the worst prognosis and they could particularly benefit from treatment with inhibitors targeting CXCR2 or CXCL8.
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Affiliation(s)
- Yutaka Yamada
- Department of Anatomic Pathology, Graduate School of Medical SciencesKyushu UniversityFukuokaJapan
- Department of Surgery and Oncology, Graduate School of Medical SciencesKyushu UniversityFukuokaJapan
| | - Takeo Yamamoto
- Department of Anatomic Pathology, Graduate School of Medical SciencesKyushu UniversityFukuokaJapan
- Department of Surgery and Oncology, Graduate School of Medical SciencesKyushu UniversityFukuokaJapan
| | - Chikanori Tsutsumi
- Department of Surgery and Oncology, Graduate School of Medical SciencesKyushu UniversityFukuokaJapan
| | - Takashi Matsumoto
- Department of Anatomic Pathology, Graduate School of Medical SciencesKyushu UniversityFukuokaJapan
- Department of Surgery and Oncology, Graduate School of Medical SciencesKyushu UniversityFukuokaJapan
| | - Shoko Noguchi
- Department of Anatomic Pathology, Graduate School of Medical SciencesKyushu UniversityFukuokaJapan
- Department of Surgery and Oncology, Graduate School of Medical SciencesKyushu UniversityFukuokaJapan
| | - Yuki Shimada
- Department of Anatomic Pathology, Graduate School of Medical SciencesKyushu UniversityFukuokaJapan
- Department of Surgery and Oncology, Graduate School of Medical SciencesKyushu UniversityFukuokaJapan
| | - Kohei Nakata
- Department of Surgery and Oncology, Graduate School of Medical SciencesKyushu UniversityFukuokaJapan
| | - Kenoki Ohuchida
- Department of Surgery and Oncology, Graduate School of Medical SciencesKyushu UniversityFukuokaJapan
| | - Masafumi Nakamura
- Department of Surgery and Oncology, Graduate School of Medical SciencesKyushu UniversityFukuokaJapan
| | - Yoshinao Oda
- Department of Anatomic Pathology, Graduate School of Medical SciencesKyushu UniversityFukuokaJapan
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Xu X, Zhang X, Kou R, Liu Y, Chen S, Li Z, Jian Z, Wang Z. Prognosis and immunotherapy response prediction based on M2 macrophage-related genes in colon cancer. J Cancer Res Clin Oncol 2024; 150:31. [PMID: 38270646 PMCID: PMC10811099 DOI: 10.1007/s00432-023-05573-6] [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: 08/04/2023] [Accepted: 12/12/2023] [Indexed: 01/26/2024]
Abstract
BACKGROUND M2 macrophage were revealed to play a crucial role in immune evasion and immunotherapies. This study aims to explore the potential significance of M2 macrophage-related genes in colon adenocarcinoma (COAD) by analysizing the transcriptome data in a comprehensive way. METHODS We collected RNA-sequencing (RNA-seq) data of COAD from The Cancer Genome Atlas (TCGA) and Gene Expression Ominibus (GEO) databases. We calculated the immune infiltration scores of every sample using CIBERSORT algorithm. Through weighted gene co-expression network analysis (WGCNA), we picked out M2 macrophage-related genes. With these genes we screened out prognosis related genes which were utilized to construct a signature to assess the prognosis of patients. To extend the potential application of the signature, we also calculated the correlations with immune infiltration. Finally, we applied techniques such as quantitative reverse transcription polymerase chain reaction (qRT-PCR) and immunoblotting (Western Blotting) to validate the RNF32 gene in cellular in vitro assays. RESULTS Seven M2 macrophage-related genes signature was constructed, which was an excellent prognostic predictor in two independent groups. The high-risk group showed lower immune infiltration and poorer response to immunotherapies than those of the low-risk group. The cell vitro experiments showed that the expression level of RNF32 was upregulated in colon cancer cell lines compared with normal cell lines. Moreover, we found that RNF32 may promote the proliferation, migration and invasion of cancer cells in vitro by inhibiting apoptosis. CONCLUSION A novel M2 macrophage-related gene signature affects the prognosis and immune characteristics of colon cancer.
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Affiliation(s)
- Xiaochen Xu
- Department of Gastrointestinal Surgery, Affiliated Hospital of Guilin Medical University, Guangxi Zhuang Autonomous Region, Guilin, 541001, China
| | - Xinwen Zhang
- Department of Gastrointestinal Surgery, Affiliated Hospital of Guilin Medical University, Guangxi Zhuang Autonomous Region, Guilin, 541001, China
| | - Ruilong Kou
- Department of Gastrointestinal Surgery, Affiliated Hospital of Guilin Medical University, Guangxi Zhuang Autonomous Region, Guilin, 541001, China
| | - Yihao Liu
- Department of Gastrointestinal Surgery, Affiliated Hospital of Guilin Medical University, Guangxi Zhuang Autonomous Region, Guilin, 541001, China
| | - Siqi Chen
- Department of Gastrointestinal Surgery, Affiliated Hospital of Guilin Medical University, Guangxi Zhuang Autonomous Region, Guilin, 541001, China
| | - Zuguo Li
- Department of Gastrointestinal Surgery, Affiliated Hospital of Guilin Medical University, Guangxi Zhuang Autonomous Region, Guilin, 541001, China
| | - Zhiyuan Jian
- Department of Gastrointestinal Surgery, Affiliated Hospital of Guilin Medical University, Guangxi Zhuang Autonomous Region, Guilin, 541001, China.
| | - Zhenran Wang
- Department of Gastrointestinal Surgery, Affiliated Hospital of Guilin Medical University, Guangxi Zhuang Autonomous Region, Guilin, 541001, China.
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Hussain Z, Bertran T, Finetti P, Lohmann E, Mamessier E, Bidaut G, Bertucci F, Rego M, Tomasini R. Macrophages reprogramming driven by cancer-associated fibroblasts under FOLFIRINOX treatment correlates with shorter survival in pancreatic cancer. Cell Commun Signal 2024; 22:1. [PMID: 38167013 PMCID: PMC10759487 DOI: 10.1186/s12964-023-01388-7] [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: 09/12/2023] [Accepted: 11/06/2023] [Indexed: 01/05/2024] Open
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) remains a clinically challenging cancer, mainly due to limited therapeutic options and the presence of a highly prominent tumor microenvironment (TME), facilitating tumor progression. The TME is predominated by heterogeneous populations of cancer-associated fibroblasts (CAFs) and tumor associated macrophages (TAMs), in constant communication with each other and with tumor cells, influencing many tumoral abilities such as therapeutic resistance. However how the crosstalk between CAFs and macrophages evolves following chemotherapeutic treatment remains poorly understood, limiting our capacity to halt therapeutic resistance. METHODS We combined biological characterization of macrophages indirectly cocultured with human PDAC CAFs, under FOLFIRINOX treatment, with mRNAseq analyses of such macrophages and evaluated the relevance of the specific gene expression signature in a large series of primary PDAC patients to search for correlation with overall survival (OS) after FOLFIRINOX chemotherapy. RESULTS Firstly, we demonstrated that CAFs polarize naïve and M1 macrophages towards an M2-like phenotype with a specific increase of CD200R and CD209 M2 markers. Then, we demonstrated that CAFs counteract the pro-inflammatory phenotype induced by the FOLFIRINOX on Macrophages. Indeed, we highlighted that, under FOLFIRINOX, CAFs limit the FOLFIRINOX-induced cell death of macrophages and further reinforce their M2 phenotype as well as their immunosuppressive impact through specific chemokines production. Finally, we revealed that under FOLFIRINOX CAFs drive a specific macrophage gene expression signature involving SELENOP and GOS2 that correlates with shortened OS in FOLFIRINOX-treated PDAC patients. CONCLUSION Our study provides insight into the complex interactions between TME cells under FOLFIRINOX treatment. It suggests potential novel candidates that could be used as therapeutic targets in combination with FOLFIRINOX to prevent and alleviate TME influx on therapeutic resistance as well as biomarkers to predict FOLFIRINOX response in PDAC patients. Video Abstract.
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Affiliation(s)
- Zainab Hussain
- Cancer Research Center of Marseille, Aix-Marseille University, INSERM U1068, CNRS UMR7258, Institute Paoli-Calmettes, Marseille, France
| | - Thomas Bertran
- Cancer Research Center of Marseille, Aix-Marseille University, INSERM U1068, CNRS UMR7258, Institute Paoli-Calmettes, Marseille, France
| | - Pascal Finetti
- Cancer Research Center of Marseille, Aix-Marseille University, INSERM U1068, CNRS UMR7258, Institute Paoli-Calmettes, Marseille, France
| | - Eugenie Lohmann
- Cancer Research Center of Marseille, Aix-Marseille University, INSERM U1068, CNRS UMR7258, Institute Paoli-Calmettes, Marseille, France
| | - Emilie Mamessier
- Cancer Research Center of Marseille, Aix-Marseille University, INSERM U1068, CNRS UMR7258, Institute Paoli-Calmettes, Marseille, France
| | - Ghislain Bidaut
- Cancer Research Center of Marseille, Aix-Marseille University, INSERM U1068, CNRS UMR7258, Institute Paoli-Calmettes, Marseille, France
| | - François Bertucci
- Cancer Research Center of Marseille, Aix-Marseille University, INSERM U1068, CNRS UMR7258, Institute Paoli-Calmettes, Marseille, France
- Department of Medical Oncology, Institut Paoli-Calmettes, Marseille, France
| | - Moacyr Rego
- Therapeutic Innovation Center, Federal University of Pernambuco, Recife, Brazil
| | - Richard Tomasini
- Cancer Research Center of Marseille, Aix-Marseille University, INSERM U1068, CNRS UMR7258, Institute Paoli-Calmettes, Marseille, France.
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Liu Z, Zhang Y, Wu C. Single-cell sequencing in pancreatic cancer research: A deeper understanding of heterogeneity and therapy. Biomed Pharmacother 2023; 168:115664. [PMID: 37837881 DOI: 10.1016/j.biopha.2023.115664] [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: 07/05/2023] [Revised: 09/28/2023] [Accepted: 10/06/2023] [Indexed: 10/16/2023] Open
Abstract
Pancreatic cancer, including pancreatic ductal adenocarcinomas (PDACs), is a malignant tumor with characteristics of tumor-stroma interactions. Patients often have a poor prognosis and a poor long-term survival rate. In recent years, rapidly-developing single-cell sequencing techniques have been used to analyze cell populations at a single-cell resolution, so that it is now possible to have a more in-depth and clearer understanding of the genetic composition of pancreatic cancer. In this review, we provide an overview of the current single-cell sequencing techniques and their applications in the exploration of intratumoral heterogeneity, the tumor microenvironment, therapy resistance, and novel treatments. Our hope is to provide new insight into the potential of precision therapy, which will perhaps one day lead to significant advances in PDAC treatment.
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Affiliation(s)
- Zhuomiao Liu
- Department of Radiation Oncology, the Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Yalin Zhang
- Department of Radiation Oncology, the Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Chunli Wu
- Department of Radiation Oncology, the Fourth Affiliated Hospital of China Medical University, Shenyang, China.
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Gao Z, Kang SW, Erstad D, Azar J, Van Buren G, Fisher W, Sun Z, Rubinstein MP, Lee HS, Camp ER. Pre-treatment inflamed tumor immune microenvironment is associated with FOLFIRINOX response in pancreatic cancer. Front Oncol 2023; 13:1274783. [PMID: 38074633 PMCID: PMC10701674 DOI: 10.3389/fonc.2023.1274783] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Accepted: 10/31/2023] [Indexed: 02/12/2024] Open
Abstract
Introduction Pancreatic adenocarcinoma (PDAC) is an aggressive tumor with limited response to both chemotherapy and immunotherapy. Pre-treatment tumor features within the tumor immune microenvironment (TiME) may influence treatment response. We hypothesized that the pre-treatment TiME composition differs between metastatic and primary lesions and would be associated with response to modified FOLFIRINOX (mFFX) or gemcitabine-based (Gem-based) therapy. Methods Using RNAseq data from a cohort of treatment-naïve, advanced PDAC patients in the COMPASS trial, differential gene expression analysis of key immunomodulatory genes in were analyzed based on multiple parameters including tumor site, response to mFFX, and response to Gem-based treatment. The relative proportions of immune cell infiltration were defined using CIBERSORTx and Dirichlet regression. Results 145 samples were included in the analysis; 83 received mFFX, 62 received Gem-based therapy. Metastatic liver samples had both increased macrophage (1.2 times more, p < 0.05) and increased eosinophil infiltration (1.4 times more, p < 0.05) compared to primary lesion samples. Further analysis of the specific macrophage phenotypes revealed an increased M2 macrophage fraction in the liver samples. The pre-treatment CD8 T-cell, dendritic cell, and neutrophil infiltration of metastatic samples were associated with therapy response to mFFX (p < 0.05), while mast cell infiltration was associated with response to Gem-based therapy (p < 0.05). Multiple immunoinhibitory genes such as ADORA2A, CSF1R, KDR/VEGFR2, LAG3, PDCD1LG2, and TGFB1 and immunostimulatory genes including C10orf54, CXCL12, and TNFSF14/LIGHT were significantly associated with worse survival in patients who received mFFX (p = 0.01). There were no immunomodulatory genes associated with survival in the Gem-based cohort. Discussion Our evidence implies that essential differences in the PDAC TiME exist between primary and metastatic tumors and an inflamed pretreatment TiME is associated with mFFX response. Defining components of the PDAC TiME that influence therapy response will provide opportunities for targeted therapeutic strategies that may need to be accounted for in designing personalized therapy to improve outcomes.
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Affiliation(s)
- Zachary Gao
- Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, United States
| | - Sung Wook Kang
- Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, United States
- Department of Surgery, Dan L. Duncan Comprehensive Cancer Center, Houston, TX, United States
- Systems Onco-Immunology Laboratory, David J. Sugarbaker Division of Thoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, United States
| | - Derek Erstad
- Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, United States
- Department of Surgery, Dan L. Duncan Comprehensive Cancer Center, Houston, TX, United States
- Department of Surgery, Michael E. DeBakey VA Medical Center, Houston, TX, United States
| | - Joseph Azar
- The Pelotonia Institute for Immuno-Oncology, Ohio State University Comprehensive Cancer Center, Columbus, OH, United States
| | - George Van Buren
- Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, United States
- Department of Surgery, Dan L. Duncan Comprehensive Cancer Center, Houston, TX, United States
| | - William Fisher
- Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, United States
- Department of Surgery, Dan L. Duncan Comprehensive Cancer Center, Houston, TX, United States
| | - Zequn Sun
- Department of Preventative Medicine, Northwestern University Clinical and Translational Sciences Institute, Chicago, IL, United States
| | - Mark P. Rubinstein
- The Pelotonia Institute for Immuno-Oncology, Ohio State University Comprehensive Cancer Center, Columbus, OH, United States
| | - Hyun-Sung Lee
- Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, United States
- Department of Surgery, Dan L. Duncan Comprehensive Cancer Center, Houston, TX, United States
- Systems Onco-Immunology Laboratory, David J. Sugarbaker Division of Thoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, United States
| | - E. Ramsay Camp
- Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, United States
- Department of Surgery, Dan L. Duncan Comprehensive Cancer Center, Houston, TX, United States
- Department of Surgery, Michael E. DeBakey VA Medical Center, Houston, TX, United States
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Zhu Z, Yi B, Tang Z, Chen X, Li M, Xu T, Zhao Z, Tang C. Lactobacillus casei combined with Lactobacillus reuteri alleviate pancreatic cancer by inhibiting TLR4 to promote macrophage M1 polarization and regulate gut microbial homeostasis. BMC Cancer 2023; 23:1044. [PMID: 37904102 PMCID: PMC10614400 DOI: 10.1186/s12885-023-11557-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Accepted: 10/22/2023] [Indexed: 11/01/2023] Open
Abstract
BACKGROUND Pancreatic cancer is a highly lethal disease with no effective treatments. Lactobacillus casei (L. casei) and Lactobacillus reuteri (L. reuteri) exhibited therapeutic effects on several cancers, but their roles in pancreatic cancer are unknown. This study aims to explore how L. casei & L. reuteri influence pancreatic cancer and the underlying mechanisms. METHODS Pancreatic cancer cells were treated with L. casei & L. reuteri and co-cultured with macrophages in a transwell system in vitro. Pancreatic cancer xenograft model was established and L. casei & L. reuteri was used to treat mice in vivo. MTT, CCK-8 assay or immunohistochemical staining were used to determine the proliferation of pancreatic cancer cells or tumor tissues. Transwell assay was applied to test the migration and invasion of pancreatic cells. RT-qPCR was utilized to assess TLR4 and MyD88 expressions in pancreatic cells or tumor tissues. WB, immunofluorescence staining, or flow cytometry was used to evaluate the M1/M2 polarization of macrophages. Besides, the composition of gut microbiota of tumor-bearing mice was determined by 16 S rRNA sequencing, and ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS) untargeted metabolomics was used to evaluate the metabolic profiles of feces. RESULTS L. casei & L. reuteri inhibited the proliferation, migration, invasion of pancreatic cancer cells and pancreatic cancer cell-induced M2 polarization of macrophages by suppressing TLR4. Meanwhile, L. casei & L. reuteri repressed pancreatic cancer growth and promoted M1 macrophage polarization. Besides, L. casei & L. reuteri reduced fecal Alloprevotella and increased fecal azelate and glutamate in nude mice, while TLR4 inhibitor TAK-242 increased Clostridia UCG-014, azelate, uridine, methionine sulfoxide, oxypurinol, and decreased glyceryl monoester in the feces of pancreatic tumor-bearing mice. Fecal oxypurinol and glyceryl monoester levels were positively or negatively associated with gut Clostridia UCG-014 abundance, respectively. CONCLUSION L. casei & L. reuteri alleviate pancreatic cancer by inhibiting TLR4 to promote macrophage M1 polarization and regulate gut microbial homeostasis.
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Affiliation(s)
- Zemin Zhu
- Department of Hepatobiliary and Pancreatic Surgery, Zhuzhou Central Hospital, Zhuzhou, China
| | - Bo Yi
- Department of Hepatobiliary and Pancreatic Surgery, Zhuzhou Central Hospital, Zhuzhou, China
| | - Zikai Tang
- Department of Hepatobiliary and Pancreatic Surgery, Zhuzhou Central Hospital, Zhuzhou, China
| | - Xun Chen
- Department of Hepatobiliary and Pancreatic Surgery, Zhuzhou Central Hospital, Zhuzhou, China
- Department of Trauma Center, Zhuzhou Central Hospital, Zhuzhou, China
| | - Ming Li
- Department of Trauma Center, Zhuzhou Central Hospital, Zhuzhou, China
| | - Tao Xu
- Department of Hepatobiliary and Pancreatic Surgery, Zhuzhou Central Hospital, Zhuzhou, China
| | - Zhijian Zhao
- Department of Hepatobiliary and Pancreatic Surgery, Zhuzhou Central Hospital, Zhuzhou, China.
| | - Caixi Tang
- Department of Hepatobiliary and Pancreatic Surgery, Zhuzhou Central Hospital, Zhuzhou, China.
- Department of Trauma Center, Zhuzhou Central Hospital, Zhuzhou, China.
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Thielman NRJ, Funes V, Davuluri S, Ibanez HE, Sun WC, Fu J, Li K, Muth S, Pan X, Fujiwara K, Thomas D, Henderson M, Teh SS, Zhu Q, Thompson E, Jaffee EM, Kolodkin A, Meng F, Zheng L. Tumor- and Nerve-Derived Axon Guidance Molecule Promotes Pancreatic Ductal Adenocarcinoma Progression and Metastasis through Macrophage Reprogramming. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.10.24.563862. [PMID: 37961340 PMCID: PMC10634802 DOI: 10.1101/2023.10.24.563862] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/15/2023]
Abstract
Axon guidance molecules were found to be the gene family most frequently altered in pancreatic ductal adenocarcinoma (PDA) through mutations and copy number changes. However, the exact molecular mechanism regarding PDA development remained unclear. Using genetically engineered mouse models to examine one of the axon guidance molecules, semaphorin 3D (SEMA3D), we found a dual role for tumor-derived SEMA3D in malignant transformation of pancreatic epithelial cells and a role for nerve-derived SEMA3D in PDA development. This was demonstrated by the pancreatic-specific knockout of the SEMA3D gene from the KRAS G12D and TP53 R 172 H mutation knock-in, PDX1-Cre (KPC) mouse model which demonstrated a delayed tumor initiation and growth comparing to the original KPC mouse model. Our results showed that SEMA3D knockout skews the macrophages in the pancreas away from M2 polarization, providing a potential mechanistic role of tumor-derived SEMA3D in PDA development. The KPC mice with the SEMA3D knockout remained metastasis-free, however, died from primary tumor growth. We then tested the hypothesis that a potential compensation mechanism could result from SEMA3D which is naturally expressed by the intratumoral nerves. Our study further revealed that nerve-derived SEMA3D does not reprogram macrophages directly, but reprograms macrophages indirectly through ARF6 signaling and lactate production in PDA tumor cells. SEMA3D increases tumor-secreted lactate which is sensed by GPCR132 on macrophages and subsequently stimulates pro-tumorigenic M2 polarization in vivo. Tumor intrinsic- and extrinsic-SEMA3D induced ARF6 signaling through its receptor Plexin D1 in a mutant KRAS-dependent manner. Consistently, RNA sequencing database analysis revealed an association of higher KRAS MUT expression with an increase in SEMA3D and ARF6 expression in human PDAs. Moreover, multiplex immunohistochemistry analysis showed an increased number of M2-polarized macrophages proximal to nerves in human PDA tissue expressing SEMA3D. Thus, this study suggests altered expression of SEMA3D in tumor cells lead to acquisition of cancer-promoting functions and the axon guidance signaling originating from nerves is "hijacked" by tumor cells to support their growth. Other axon guidance and neuronal development molecules may play a similar dual role which is worth further investigation. One sentence summary Tumor- and nerve-derived SEMA3D promotes tumor progression and metastasis through macrophage reprogramming in the tumor microenvironment. STATEMENT OF SIGNIFICANCE This study established the dual role of axon guidance molecule, SEMA3D, in the malignant transformation of pancreatic epithelial cells and of nerve-derived SEMA3D in PDA progression and metastasis. It revealed macrophage reprogramming as the mechanism underlying bothroles. Together, this research elucidated how inflammatory responses promote invasive PDA progression and metastasis through an oncogenic process.
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Yang T, Han Y, Chen J, Liang X, Sun L. MiR-506 Promotes Antitumor Immune Response in Pancreatic Cancer by Reprogramming Tumor-Associated Macrophages toward an M1 Phenotype. Biomedicines 2023; 11:2874. [PMID: 38001876 PMCID: PMC10669181 DOI: 10.3390/biomedicines11112874] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Revised: 10/03/2023] [Accepted: 10/10/2023] [Indexed: 11/26/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant cancer with a poor prognosis, and effective treatments for PDAC are lacking. In this study, we hypothesized that miR-506 promotes antitumor immune response in PDAC by reprogramming tumor-associated macrophages toward an M1 phenotype to reverse its immunosuppressive tumor microenvironment (TME). First, the relationship between TME and the expression of miR-506 was assessed using clinical samples. Our results provided evidence that lower expression of miR-506 was associated with poor prognosis and immunosuppressive TME in PDAC patients. In addition, miR-506 inhibit the PDAC progression and reversed its immunosuppressive microenvironment in a macrophage-dependent manner. Next, we established a PDAC mouse model by orthotopic injection to further explore the role of miR-506 in vivo. Mechanistic investigations demonstrated that miR-506 could reprogram the polarization of M2-like macrophages toward an M1-like phenotype through targeting STAT3. Meanwhile, miR-506 could also sensitize PDAC to anti-PD-1 immunotherapy, because the tumor microenvironment remodeling effects of miR-506 could reprogram macrophage polarization and subsequently promote cytotoxic T lymphocyte (CTL) infiltration. These findings suggest a relationship between miR-506 and TME, especially M2-like macrophages, thus providing novel insights into mechanisms of tumor progression and potential immunotherapeutic targets for further clinical treatment.
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Affiliation(s)
| | | | | | | | - Longhao Sun
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin 300052, China (X.L.)
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19
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Yousuf S, Qiu M, Voith von Voithenberg L, Hulkkonen J, Macinkovic I, Schulz AR, Hartmann D, Mueller F, Mijatovic M, Ibberson D, AlHalabi KT, Hetzer J, Anders S, Brüne B, Mei HE, Imbusch CD, Brors B, Heikenwälder M, Gaida MM, Büchler MW, Weigert A, Hackert T, Roth S. Spatially Resolved Multi-Omics Single-Cell Analyses Inform Mechanisms of Immune Dysfunction in Pancreatic Cancer. Gastroenterology 2023; 165:891-908.e14. [PMID: 37263303 DOI: 10.1053/j.gastro.2023.05.036] [Citation(s) in RCA: 33] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2022] [Revised: 05/22/2023] [Accepted: 05/23/2023] [Indexed: 06/03/2023]
Abstract
BACKGROUND & AIMS As pancreatic ductal adenocarcinoma (PDAC) continues to be recalcitrant to therapeutic interventions, including poor response to immunotherapy, albeit effective in other solid malignancies, a more nuanced understanding of the immune microenvironment in PDAC is urgently needed. We aimed to unveil a detailed view of the immune micromilieu in PDAC using a spatially resolved multimodal single-cell approach. METHODS We applied single-cell RNA sequencing, spatial transcriptomics, multiplex immunohistochemistry, and mass cytometry to profile the immune compartment in treatment-naïve PDAC tumors and matched adjacent normal pancreatic tissue, as well as in the systemic circulation. We determined prognostic associations of immune signatures and performed a meta-analysis of the immune microenvironment in PDAC and lung adenocarcinoma on single-cell level. RESULTS We provided a spatially resolved fine map of the immune landscape in PDAC. We substantiated the exhausted phenotype of CD8 T cells and immunosuppressive features of myeloid cells, and highlighted immune subsets with potentially underappreciated roles in PDAC that diverged from immune populations within adjacent normal areas, particularly CD4 T cell subsets and natural killer T cells that are terminally exhausted and acquire a regulatory phenotype. Differential analysis of immune phenotypes in PDAC and lung adenocarcinoma revealed the presence of extraordinarily immunosuppressive subtypes in PDAC, along with a distinctive immune checkpoint composition. CONCLUSIONS Our study sheds light on the multilayered immune dysfunction in PDAC and presents a holistic view of the immune landscape in PDAC and lung adenocarcinoma, providing a comprehensive resource for functional studies and the exploration of therapeutically actionable targets in PDAC.
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Affiliation(s)
- Suhail Yousuf
- Department of Surgery, Heidelberg University Hospital, Heidelberg, Germany
| | - Mengjie Qiu
- Department of Surgery, Heidelberg University Hospital, Heidelberg, Germany
| | | | - Johannes Hulkkonen
- Department of Surgery, Heidelberg University Hospital, Heidelberg, Germany
| | - Igor Macinkovic
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, Frankfurt, Germany
| | | | - Domenic Hartmann
- Department of Surgery, Heidelberg University Hospital, Heidelberg, Germany
| | - Florian Mueller
- Division of Chronic Inflammation and Cancer, German Cancer Research Center, Heidelberg, Germany
| | - Margarete Mijatovic
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, Frankfurt, Germany
| | - David Ibberson
- Deep Sequencing Core Facility, BioQuant, Heidelberg University, Heidelberg, Germany
| | - Karam T AlHalabi
- Department of Surgery, Heidelberg University Hospital, Heidelberg, Germany
| | - Jenny Hetzer
- Division of Chronic Inflammation and Cancer, German Cancer Research Center, Heidelberg, Germany
| | - Simon Anders
- BioQuant Center, Heidelberg University, Heidelberg, Germany
| | - Bernhard Brüne
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, Frankfurt, Germany; Frankfurt Cancer Institute, Goethe-University Frankfurt, Frankfurt, Germany; German Cancer Consortium, Partner Site Frankfurt, Germany
| | - Henrik E Mei
- German Rheumatism Research Center, Berlin, Germany
| | - Charles D Imbusch
- Division of Applied Bioinformatics, German Cancer Research Center, Heidelberg, Germany
| | - Benedikt Brors
- Division of Applied Bioinformatics, German Cancer Research Center, Heidelberg, Germany
| | - Mathias Heikenwälder
- Division of Chronic Inflammation and Cancer, German Cancer Research Center, Heidelberg, Germany
| | - Matthias M Gaida
- Institute of Pathology, University Medical Center Mainz, Johannes Gutenberg University, Mainz, Germany; Research Center for Immunotherapy, University Medical Center Mainz, Johannes Gutenberg University, Mainz, Germany; Joint Unit Immunopathology, Institute of Pathology, University Medical Center, Johannes Gutenberg University and Translational Oncology, University Medical Center Mainz, Mainz, Germany
| | - Markus W Büchler
- Department of Surgery, Heidelberg University Hospital, Heidelberg, Germany
| | - Andreas Weigert
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, Frankfurt, Germany; Frankfurt Cancer Institute, Goethe-University Frankfurt, Frankfurt, Germany; German Cancer Consortium, Partner Site Frankfurt, Germany
| | - Thilo Hackert
- Department of Surgery, Heidelberg University Hospital, Heidelberg, Germany
| | - Susanne Roth
- Department of Surgery, Heidelberg University Hospital, Heidelberg, Germany.
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20
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Zhang B, Sun J, Guan H, Guo H, Huang B, Chen X, Chen F, Yuan Q. Integrated single-cell and bulk RNA sequencing revealed the molecular characteristics and prognostic roles of neutrophils in pancreatic cancer. Aging (Albany NY) 2023; 15:9718-9742. [PMID: 37728418 PMCID: PMC10564426 DOI: 10.18632/aging.205044] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Accepted: 08/21/2023] [Indexed: 09/21/2023]
Abstract
Pancreatic cancer, one of the most prevalent tumors of the digestive system, has a dismal prognosis. Cancer of the pancreas is distinguished by an inflammatory tumor microenvironment rich in fibroblasts and different immune cells. Neutrophils are important immune cells that infiltrate the microenvironment of pancreatic cancer tumors. The purpose of this work was to examine the complex mechanism by which neutrophils influence the carcinogenesis and development of pancreatic cancer and to construct a survival prediction model based on neutrophil marker genes. We incorporated the GSE111672 dataset, comprising RNA expression data from 27,000 cells obtained from 3 patients with PC, and conducted single-cell data analysis. Thorough investigation of pancreatic cancer single-cell RNA sequencing data found 350 neutrophil marker genes. Using The Cancer Genome Atlas (TCGA), GSE28735, GSE62452, GSE57495, and GSE85916 datasets to gather pancreatic cancer tissue transcriptome data, and consistent clustering was used to identify two categories for analyzing the influence of neutrophils on pancreatic cancer. Using the Random Forest algorithm and Cox regression analysis, a survival prediction model for pancreatic cancer was developed, the model showed independent performance for survival prognosis, clinic pathological features, immune infiltration, and drug sensitivity. Multivariate Cox analysis findings revealed that the risk scores derived from predictive models is independent prognostic markers for pancreatic patients. In conclusion, based on neutrophil marker genes, this research created a molecular typing and prognostic grading system for pancreatic cancer, this system was very accurate in predicting the prognosis, tumor immune microenvironment status, and pharmacological treatment responsiveness of pancreatic cancer patients.
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Affiliation(s)
- Biao Zhang
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Jiaao Sun
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Hewen Guan
- Department of Dermatology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Hui Guo
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Bingqian Huang
- Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, Liaoning, China
| | - Xu Chen
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Feng Chen
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Qihang Yuan
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
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21
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Urbanova M, Cihova M, Buocikova V, Slopovsky J, Dubovan P, Pindak D, Tomas M, García-Bermejo L, Rodríguez-Garrote M, Earl J, Kohl Y, Kataki A, Dusinska M, Sainz B, Smolkova B, Gabelova A. Nanomedicine and epigenetics: New alliances to increase the odds in pancreatic cancer survival. Biomed Pharmacother 2023; 165:115179. [PMID: 37481927 DOI: 10.1016/j.biopha.2023.115179] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Revised: 07/04/2023] [Accepted: 07/12/2023] [Indexed: 07/25/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest cancers worldwide, primarily due to its robust desmoplastic stroma and immunosuppressive tumor microenvironment (TME), which facilitate tumor progression and metastasis. In addition, fibrous tissue leads to sparse vasculature, high interstitial fluid pressure, and hypoxia, thereby hindering effective systemic drug delivery and immune cell infiltration. Thus, remodeling the TME to enhance tumor perfusion, increase drug retention, and reverse immunosuppression has become a key therapeutic strategy. In recent years, targeting epigenetic pathways has emerged as a promising approach to overcome tumor immunosuppression and cancer progression. Moreover, the progress in nanotechnology has provided new opportunities for enhancing the efficacy of conventional and epigenetic drugs. Nano-based drug delivery systems (NDDSs) offer several advantages, including improved drug pharmacokinetics, enhanced tumor penetration, and reduced systemic toxicity. Smart NDDSs enable precise targeting of stromal components and augment the effectiveness of immunotherapy through multiple drug delivery options. This review offers an overview of the latest nano-based approaches developed to achieve superior therapeutic efficacy and overcome drug resistance. We specifically focus on the TME and epigenetic-targeted therapies in the context of PDAC, discussing the advantages and limitations of current strategies while highlighting promising new developments. By emphasizing the immense potential of NDDSs in improving therapeutic outcomes in PDAC, our review paves the way for future research in this rapidly evolving field.
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Affiliation(s)
- Maria Urbanova
- Department of Molecular Oncology, Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Dubravska Cesta 9, 845 05 Bratislava, Slovakia
| | - Marina Cihova
- Department of Molecular Oncology, Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Dubravska Cesta 9, 845 05 Bratislava, Slovakia
| | - Verona Buocikova
- Department of Molecular Oncology, Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Dubravska Cesta 9, 845 05 Bratislava, Slovakia
| | - Jan Slopovsky
- 2nd Department of Oncology, National Cancer Institute, Klenova 1, 833 10 Bratislava, Slovakia; Faculty of Medicine, Comenius University, Spitalska 24, 813 72 Bratislava, Slovakia
| | - Peter Dubovan
- Department of Molecular Oncology, Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Dubravska Cesta 9, 845 05 Bratislava, Slovakia; Department of Surgical Oncology, National CancerInstitute in Bratislava, Klenova 1, 833 10 Bratislava, Slovakia; Faculty of Medicine, Slovak Medical University in Bratislava, Limbová12, 833 03 Bratislava
| | - Daniel Pindak
- Department of Surgical Oncology, National CancerInstitute in Bratislava, Klenova 1, 833 10 Bratislava, Slovakia; Faculty of Medicine, Slovak Medical University in Bratislava, Limbová12, 833 03 Bratislava
| | - Miroslav Tomas
- Department of Molecular Oncology, Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Dubravska Cesta 9, 845 05 Bratislava, Slovakia; Department of Surgical Oncology, National CancerInstitute in Bratislava, Klenova 1, 833 10 Bratislava, Slovakia; Faculty of Medicine, Slovak Medical University in Bratislava, Limbová12, 833 03 Bratislava
| | - Laura García-Bermejo
- Biomarkers and Therapeutic Targets Group, Area4, Ramón y Cajal Health Research Institute (IRYCIS), Carretera Colmenar Km 9100, 28034 Madrid, Spain
| | - Mercedes Rodríguez-Garrote
- Molecular Epidemiology and Predictive Tumor Markers Group, Area 3, Ramón y Cajal Health Research Institute (IRYCIS), Carretera Colmenar Km 9100, 28034 Madrid, Spain; CIBERONC, Madrid, Spain
| | - Julie Earl
- Molecular Epidemiology and Predictive Tumor Markers Group, Area 3, Ramón y Cajal Health Research Institute (IRYCIS), Carretera Colmenar Km 9100, 28034 Madrid, Spain; CIBERONC, Madrid, Spain
| | - Yvonne Kohl
- Department Bioprocessing & Bioanalytics, Fraunhofer Institute for Biomedical Engineering IBMT, 66280 Sulzbach, Germany
| | - Agapi Kataki
- 1st Department of Propaedeutic Surgery, National and Kapodistrian University of Athens, Vasilissis Sofias 114, 11527 Athens, Greece
| | - Maria Dusinska
- Health Effects Laboratory, Department of Environmental Chemistry, NILU-Norwegian Institute for Air Research, Instituttveien 18, 2002 Kjeller, Norway
| | - Bruno Sainz
- CIBERONC, Madrid, Spain; Instituto de Investigaciones Biomédicas"Alberto Sols" (IIBM), CSIC-UAM, 28029 Madrid, Spain; Biomarkers and Personalized Approach to Cancer (BIOPAC) Group, Area 3, Ramón y Cajal Health Research Institute (IRYCIS), 28034 Madrid, Spain
| | - Bozena Smolkova
- Department of Molecular Oncology, Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Dubravska Cesta 9, 845 05 Bratislava, Slovakia
| | - Alena Gabelova
- Department of Nanobiology, Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Dubravska Cesta 9, 84505 Bratislava, Slovakia..
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22
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Xu X, Cui L, Zhang L, Yang L, Zhuo Y, Li C. Saikosaponin d modulates the polarization of tumor-associated macrophages by deactivating the PI3K/AKT/mTOR pathway in murine models of pancreatic cancer. Int Immunopharmacol 2023; 122:110579. [PMID: 37433245 DOI: 10.1016/j.intimp.2023.110579] [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: 01/28/2023] [Revised: 06/13/2023] [Accepted: 06/24/2023] [Indexed: 07/13/2023]
Abstract
The tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) poses a major obstacle to traditional and immunomodulatory cancer therapies and is closely associated with macrophage polarization. Saikosaponin d (SSd), a major active component of triterpene saponins derived from Bupleurum falcatum, has anti-inflammatory and antitumor activities. However, whether SSd can regulate immune cells during the development of the TME in PDAC remains unknown. In the present study, we aimed to analyze the role of SSd in regulating immune cells in the PDAC TME, especially the polarization of macrophages, and examine the related mechanisms. An orthotopic PDAC cancer model was used to investigate the antitumor activities and the regulation of immune cells in vivo. In vitro, bone marrow mononuclear (BM-MNC) cells and RAW 264.7 cells were used to induce the M2 macrophage phenotype and examine the effects and molecular mechanism of SSd on M2 macrophage polarization. The results revealed that SSd could directly inhibit the apoptosis and invasion of pancreatic cancer cells, modulate the immunosuppressive microenvironment and reactivate the local immune response, especially by decreasing the shift toward M2 macrophage polarization by downregulating phosphorylated STAT6 levels and the PI3K/AKT/mTOR signaling pathway. Furthermore, 740-Y-P (PI3K activator) was used to verify that SSd inhibited M2 polarization in RAW264.7 cells via the PI3K/AKT/mTOR signaling pathway. In conclusion, this study provided experimental evidence of the antitumor effect of SSd, especially in the regulation of M2 macrophage polarization, and demonstrated that SSd may be a promising therapeutic agent in PDAC.
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Affiliation(s)
- Xinsheng Xu
- Hepatopancreatobiliary Surgery Department, Tianjin Nankai Hospital, Nankai Clinical College, Tianjin Medical University, Tianjin, China
| | - Lihua Cui
- Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Institute of Acute Abdominal Diseases of Integrated Traditional Chinese and Western Medicine, Tianjin Nankai Hospital, Nankai Clinical College, Tianjin Medical University, Tianjin, China
| | - Lanqiu Zhang
- Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Institute of Acute Abdominal Diseases of Integrated Traditional Chinese and Western Medicine, Tianjin Nankai Hospital, Nankai Clinical College, Tianjin Medical University, Tianjin, China
| | - Lei Yang
- Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Institute of Acute Abdominal Diseases of Integrated Traditional Chinese and Western Medicine, Tianjin Nankai Hospital, Nankai Clinical College, Tianjin Medical University, Tianjin, China
| | - Yuzhen Zhuo
- Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Institute of Acute Abdominal Diseases of Integrated Traditional Chinese and Western Medicine, Tianjin Nankai Hospital, Nankai Clinical College, Tianjin Medical University, Tianjin, China
| | - Caixia Li
- Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Institute of Acute Abdominal Diseases of Integrated Traditional Chinese and Western Medicine, Tianjin Nankai Hospital, Nankai Clinical College, Tianjin Medical University, Tianjin, China.
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23
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Pea A, Paolino G, Martelli F, Bariani E, Piccoli P, Sereni E, Salvia R, Lawlor RT, Cheng L, Chang D, Scarpa A, Luchini C. Characterization and digital spatial deconvolution of the immune microenvironment of intraductal oncocytic papillary neoplasms (IOPN) of the pancreas. Virchows Arch 2023; 483:157-165. [PMID: 37086293 PMCID: PMC10412653 DOI: 10.1007/s00428-023-03543-4] [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: 01/18/2023] [Revised: 03/27/2023] [Accepted: 04/07/2023] [Indexed: 04/23/2023]
Abstract
Intraductal oncocytic papillary neoplasm (IOPN) of the pancreas is a distinct entity from intraductal papillary mucinous neoplasms (IPMNs) and is considered one of the precursor lesions of pancreatic cancer. Through immunohistochemistry (IHC) and an artificial intelligence (AI)-based approach, this study aims at characterizing its immune microenvironment. Whole-slide IHC was performed on a cohort of 15 IOPNs, 2 of which harboring an associated adenocarcinoma. The following markers were tested: CD3, CD4, CD8, CD20, CD68, CD163, PD-1, PD-L1, MLH1, PMS2, MSH2, and MSH6. The main findings can be summarized as follows: (i) CD8+ T lymphocytes were the predominant immune cells (p < 0.01); (ii) the vast majority of macrophages were concurrently CD68+ and CD163+; (iii) all tumors showed an activated PD-1/PD-L1 axis, but none had mismatch repair deficiency; (iv) AI-based analysis revealed the presence of 2 distinct regions in each case, namely, Re1, localized at the center of the tumor, and Re2, located at tumor periphery; (v) the infiltrating component of the 2 invasive IOPNs showed a smaller extent of Re1 and a reduced rate of CD4+ cells, as well as a larger extent of Re2 and increased rate of CD8+ cells. IOPNs are lesions enriched in immune cells, with a predominance of CD8+ T lymphocytes and class 2 macrophages. Differently from IPMN-oncogenesis, the progression towards invasive carcinoma is accompanied by an increased rate of CD8+ lymphocytes. This finding may suggest the presence of an active self-immune surveillance in invasive IOPNs, potentially explaining, at least in part, the excellent survival rate of IOPN patients.
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Affiliation(s)
- Antonio Pea
- Department of Surgery, the Pancreas Institute, University and Hospital Trust of Verona, 37134, Verona, Italy
- The Institute of Cancer Sciences, University of Glasgow, G128QQ, Glasgow, UK
| | - Gaetano Paolino
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, 37134, Verona, Italy
| | - Filippo Martelli
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, 37134, Verona, Italy
| | - Elena Bariani
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, 37134, Verona, Italy
| | - Paola Piccoli
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, 37134, Verona, Italy
| | - Elisabetta Sereni
- Department of Surgery, the Pancreas Institute, University and Hospital Trust of Verona, 37134, Verona, Italy
| | - Roberto Salvia
- Department of Surgery, the Pancreas Institute, University and Hospital Trust of Verona, 37134, Verona, Italy
| | - Rita T Lawlor
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, 37134, Verona, Italy
- ARC-Net Research Center, University and Hospital Trust of Verona, 37134, Verona, Italy
| | - Liang Cheng
- Department of Pathology and Laboratory Medicine, Brown University Warren Alpert Medical School, Lifespan Academic Medical Center, and the Legorreta Cancer Center at Brown University, Providence, RI, 02903, USA
| | - David Chang
- The Institute of Cancer Sciences, University of Glasgow, G128QQ, Glasgow, UK
- West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, G40SF, Glasgow, UK
| | - Aldo Scarpa
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, 37134, Verona, Italy
- ARC-Net Research Center, University and Hospital Trust of Verona, 37134, Verona, Italy
| | - Claudio Luchini
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, 37134, Verona, Italy.
- ARC-Net Research Center, University and Hospital Trust of Verona, 37134, Verona, Italy.
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24
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Giustarini G, Teng G, Pavesi A, Adriani G. Characterization of 3D heterocellular spheroids of pancreatic ductal adenocarcinoma for the study of cell interactions in the tumor immune microenvironment. Front Oncol 2023; 13:1156769. [PMID: 37519820 PMCID: PMC10375712 DOI: 10.3389/fonc.2023.1156769] [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: 02/01/2023] [Accepted: 06/27/2023] [Indexed: 08/01/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies nowadays. The available chemo- and immunotherapies are often ineffective in treating PDAC due to its immunosuppressive and highly desmoplastic tumor immune microenvironment (TIME), which is hardly reproduced in the existing preclinical models. The PDAC TIME results from a peculiar spatial organization between different cell types. For this reason, developing new human models recapitulating the tissue organization and cell heterogeneity of PDAC is highly desirable. We developed human 3D heterocellular tumor spheroids of PDAC formed by cancer cells, endothelial cells, pancreatic stellate cells (PSC), and monocytes. As a control, we formed spheroids using immortalized epithelial pancreatic ductal cells (non-cancerous spheroids) with cellular heterogeneity similar to the tumor spheroids. Normal spheroids containing endothelial cells formed a complex 3D endothelial network significantly compromised in tumor spheroids. Monocyte/macrophages within the 4-culture tumor spheroids were characterized by a higher expression of CD163, CD206, PD-L1, and CD40 than those in the non-cancerous spheroids suggesting their differentiation towards an immunosuppressive phenotype. The heterocellular tumor spheroids presented a hypoxic core populated with PSC and monocytes/macrophages. The 4-culture tumor spheroids were characterized by spatial proximity of PSC and monocytes to the endothelial cells and a cytokine signature with increased concentrations of CXCL10, CCL2, and IL-6, which have been observed in PDAC patients and associated with poor survival. Further, 4-culture tumor spheroids decreased the concentrations of T-cell chemoattracting cytokines, i.e., CCL4, CCL5, and CXCL9, when compared with the non-cancerous spheroids, revealing a critical immunosuppressive feature of the different types of cells forming the tumor spheroids. Our results showed that the 4-culture tumor spheroids better resembled some critical features of patients' PDAC TIME than monoculture tumor spheroids. Using the proposed human 3D spheroid model for therapy testing at the preclinical stage may reveal pitfalls of chemo- and immuno-therapies to help the development of better anti-tumor therapies.
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Affiliation(s)
- Giulio Giustarini
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (ASTAR), Singapore, Singapore
| | - Germaine Teng
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (ASTAR), Singapore, Singapore
| | - Andrea Pavesi
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (ASTAR), Singapore, Singapore
- Mechanobiology Institute, National University of Singapore, Singapore, Singapore
| | - Giulia Adriani
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (ASTAR), Singapore, Singapore
- Department of Biomedical Engineering, National University of Singapore, Singapore, Singapore
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Lin HJ, Liu Y, Caroland K, Lin J. Polarization of Cancer-Associated Macrophages Maneuver Neoplastic Attributes of Pancreatic Ductal Adenocarcinoma. Cancers (Basel) 2023; 15:3507. [PMID: 37444617 DOI: 10.3390/cancers15133507] [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: 05/31/2023] [Revised: 07/01/2023] [Accepted: 07/03/2023] [Indexed: 07/15/2023] Open
Abstract
Mounting evidence links the phenomenon of enhanced recruitment of tumor-associated macrophages towards cancer bulks to neoplastic growth, invasion, metastasis, immune escape, matrix remodeling, and therapeutic resistance. In the context of cancer progression, naïve macrophages are polarized into M1 or M2 subtypes according to their differentiation status, gene signatures, and functional roles. While the former render proinflammatory and anticancer effects, the latter subpopulation elicits an opposite impact on pancreatic ductal adenocarcinoma. M2 macrophages have gained increasing attention as they are largely responsible for molding an immune-suppressive landscape. Through positive feedback circuits involving a paracrine manner, M2 macrophages can be amplified by and synergized with neighboring neoplastic cells, fibroblasts, endothelial cells, and non-cell autonomous constituents in the microenvironmental niche to promote an advanced disease state. This review delineates the molecular cues expanding M2 populations that subsequently convey notorious clinical outcomes. Future therapeutic regimens shall comprise protocols attempting to abolish environmental niches favoring M2 polarization; weaken cancer growth typically assisted by M2; promote the recruitment of tumoricidal CD8+ T lymphocytes and dendritic cells; and boost susceptibility towards gemcitabine as well as other chemotherapeutic agents.
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Affiliation(s)
- Huey-Jen Lin
- Department of Medical & Molecular Sciences, University of Delaware, Willard Hall Education Building, 16 West Main Street, Newark, DE 19716, USA
| | - Yingguang Liu
- Department of Molecular and Cellular Sciences, College of Osteopathic Medicine, Liberty University, 306 Liberty View Lane, Lynchburg, VA 24502, USA
| | - Kailey Caroland
- Department of Biochemistry and Molecular Biology, Molecular Medicine Graduate Program, Greenebaum Comprehensive Cancer Center, School of Medicine, University of Maryland, 108 N. Greene Street, Baltimore, MD 21201, USA
| | - Jiayuh Lin
- Department of Biochemistry and Molecular Biology, Molecular Medicine Graduate Program, Greenebaum Comprehensive Cancer Center, School of Medicine, University of Maryland, 108 N. Greene Street, Baltimore, MD 21201, USA
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26
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Chang J, Lo ZHY, Alenizi S, Kovacevic Z. Re-Shaping the Pancreatic Cancer Tumor Microenvironment: A New Role for the Metastasis Suppressor NDRG1. Cancers (Basel) 2023; 15:2779. [PMID: 37345116 DOI: 10.3390/cancers15102779] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 05/01/2023] [Accepted: 05/05/2023] [Indexed: 06/23/2023] Open
Abstract
Pancreatic cancer (PaC) is a highly aggressive disease, with poor response to current treatments and 5-year survival rates of 10-15%. PaC progression is facilitated by its interaction with the complex and multifaceted tumor microenvironment (TME). In the TME, cancer cells and surrounding stromal cells constantly communicate with each other via the secretion and uptake of factors including cytokines, chemokines, growth factors, metabolites, and extracellular vesicles (EVs), reshaping the landscape of PaC. Recent studies demonstrated that the metastasis suppressor N-myc downstream regulated 1 (NDRG1) not only inhibits oncogenic signaling pathways in PaC cells but also alters the communication between PaC cells and the surrounding stroma. In fact, NDRG1 was found to influence the secretome of PaC cells, alter cancer cell metabolism, and interfere with intracellular trafficking and intercellular communication between PaC cells and surrounding fibroblasts. This review will present recent advancements in understanding the role of NDRG1 in PaC progression, with a focus on how this molecule influences PaC-stroma communication and its potential for re-shaping the PaC TME.
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Affiliation(s)
- Jiawei Chang
- School of Medical Sciences, Faculty of Medicine & Health, University of Sydney, Sydney 2006, Australia
- Department of Physiology, School of Biomedical Sciences, Faculty of Medicine & Health, University of NSW, Sydney 2052, Australia
| | - Zoe H Y Lo
- School of Medical Sciences, Faculty of Medicine & Health, University of Sydney, Sydney 2006, Australia
| | - Shafi Alenizi
- School of Medical Sciences, Faculty of Medicine & Health, University of Sydney, Sydney 2006, Australia
| | - Zaklina Kovacevic
- School of Medical Sciences, Faculty of Medicine & Health, University of Sydney, Sydney 2006, Australia
- Department of Physiology, School of Biomedical Sciences, Faculty of Medicine & Health, University of NSW, Sydney 2052, Australia
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27
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Stouten I, van Montfoort N, Hawinkels LJAC. The Tango between Cancer-Associated Fibroblasts (CAFs) and Immune Cells in Affecting Immunotherapy Efficacy in Pancreatic Cancer. Int J Mol Sci 2023; 24:ijms24108707. [PMID: 37240052 DOI: 10.3390/ijms24108707] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 05/09/2023] [Accepted: 05/11/2023] [Indexed: 05/28/2023] Open
Abstract
The lack of response to therapy in pancreatic ductal adenocarcinoma (PDAC) patients has contributed to PDAC having one of the lowest survival rates of all cancer types. The poor survival of PDAC patients urges the exploration of novel treatment strategies. Immunotherapy has shown promising results in several other cancer types, but it is still ineffective in PDAC. What sets PDAC apart from other cancer types is its tumour microenvironment (TME) with desmoplasia and low immune infiltration and activity. The most abundant cell type in the TME, cancer-associated fibroblasts (CAFs), could be instrumental in why low immunotherapy responses are observed. CAF heterogeneity and interactions with components of the TME is an emerging field of research, where many paths are to be explored. Understanding CAF-immune cell interactions in the TME might pave the way to optimize immunotherapy efficacy for PDAC and related cancers with stromal abundance. In this review, we discuss recent discoveries on the functions and interactions of CAFs and how targeting CAFs might improve immunotherapy.
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Affiliation(s)
- Imke Stouten
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
| | - Nadine van Montfoort
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
| | - Lukas J A C Hawinkels
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
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28
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Closa D. Pancreatic cancer, stroma, and exosomes. J Physiol Biochem 2023; 79:205-211. [PMID: 35644825 PMCID: PMC9905168 DOI: 10.1007/s13105-022-00898-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Accepted: 05/17/2022] [Indexed: 02/08/2023]
Abstract
In the pathogenesis of pancreatic adenocarcinoma, tumor stroma plays a key role in both aggressiveness, immune evasion, resistance to chemotherapy, and the ability to metastasize. Among the elements that characterize the behavior of the stroma, extracellular vesicles and, in particular, exosomes play an important role. These extracellular vesicles carry a wide range of bioactive molecules, from transcription factors to microRNAs, which can substantially alter the phenotype of the cellular components of the stroma. Exosomes are involved in the exchange of signals between tumor cells, tumor-associated macrophages, cancer-associated fibroblasts, and also with the healthy cells surrounding the tumor. They can transfer resistance to chemotherapeutic drugs, promote the epithelial-mesenchymal transition, modify the phenotype of macrophages, or induce the expression of molecules that alter the extracellular matrix to facilitate migration and metastasis. On the other hand, all these characteristics make these vesicles first-rate therapeutic targets, as controlling their functionality could greatly enhance the effectiveness of treatments that, today, are still far from be satisfactory.
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Affiliation(s)
- Daniel Closa
- Dept. Experimental Pathology, IIBB-CSIC-IDIBAPS, Barcelona, Spain.
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29
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The Senescence-Related Signature Predicts Prognosis and Characterization of Tumor Microenvironment Infiltration in Pancreatic Cancer. BIOMED RESEARCH INTERNATIONAL 2022; 2022:1916787. [DOI: 10.1155/2022/1916787] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 10/05/2022] [Indexed: 12/12/2022]
Abstract
Background. Senescence is thought to be an imperative effect on the development of cancer. However, few studies pay an attention to the senescence-associated genes in pancreatic cancer (PC). The prognostic value of senescence-related genes (SRGs) and their involvement in tumor microenvironment (TME) in the PC remain obscure. The aim of this research was to investigate the prognostic role of senescence-associated genes and their affection in TME in PC. Methods. The transcriptome and clinical information of PC patients were obtained from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. Two SRG-mediated molecular clusters were comprehensively identified. In total, data from the 285 PC patients were randomly used to develop a senescence-associated gene signature in the training set and verified in the validation set. Immune microenvironment analysis pertained to senescence-related genes was performed. Results. A SRG_score including five senescence-associated genes was established to separate PC patients into two risk groups. High-risk patients had worse overall survival than low-risk patients. The result of the multivariate Cox regression analysis identified the risk score and stage as independent prognostic factors for PC patients. Receiver operating characteristic curve (ROC) analysis confirmed the credible predictive ability of the nomogram. The area under time-dependent ROC curve (AUC) reached 0.746 at 1 year, 0.781 at 3 years, and 0.868 at 5 years in the training set and 0.653 at 1 year, 0.755 at 3 years, and 0.785 at 5 years in the validation set. Moreover, the SRG_score was associated with TME, tumor mutation burden (TMB), and chemotherapeutic drug sensitivity. Conclusions. This study found that the novel SRG_score could be an independent prognostic target for PC patients. Senescence-associated genes had a vital impact on the immune microenvironment and the treatment of PC patients.
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Hashimoto A, Handa H, Hata S, Hashimoto S. Orchestration of mesenchymal plasticity and immune evasiveness via rewiring of the metabolic program in pancreatic ductal adenocarcinoma. Front Oncol 2022; 12:1005566. [PMID: 36408139 PMCID: PMC9669439 DOI: 10.3389/fonc.2022.1005566] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Accepted: 10/18/2022] [Indexed: 11/05/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most fatal cancer in humans, due to its difficulty of early detection and its high metastatic ability. The occurrence of epithelial to mesenchymal transition in preinvasive pancreatic lesions has been implicated in the early dissemination, drug resistance, and cancer stemness of PDAC. PDAC cells also have a reprogrammed metabolism, regulated by driver mutation-mediated pathways, a desmoplastic tumor microenvironment (TME), and interactions with stromal cells, including pancreatic stellate cells, fibroblasts, endothelial cells, and immune cells. Such metabolic reprogramming and its functional metabolites lead to enhanced mesenchymal plasticity, and creates an acidic and immunosuppressive TME, resulting in the augmentation of protumor immunity via cancer-associated inflammation. In this review, we summarize our recent understanding of how PDAC cells acquire and augment mesenchymal features via metabolic and immunological changes during tumor progression, and how mesenchymal malignancies induce metabolic network rewiring and facilitate an immune evasive TME. In addition, we also present our recent findings on the interesting relevance of the small G protein ADP-ribosylation factor 6-based signaling pathway driven by KRAS/TP53 mutations, inflammatory amplification signals mediated by the proinflammatory cytokine interleukin 6 and RNA-binding protein ARID5A on PDAC metabolic reprogramming and immune evasion, and finally discuss potential therapeutic strategies for the quasi-mesenchymal subtype of PDAC.
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Affiliation(s)
- Ari Hashimoto
- Department of Molecular Biology, Hokkaido University Faculty of Medicine, Sapporo, Japan
- *Correspondence: Ari Hashimoto, ; Shigeru Hashimoto,
| | - Haruka Handa
- Department of Molecular Biology, Hokkaido University Faculty of Medicine, Sapporo, Japan
| | - Soichiro Hata
- Department of Molecular Biology, Hokkaido University Faculty of Medicine, Sapporo, Japan
| | - Shigeru Hashimoto
- Division of Molecular Psychoimmunology, Institute for Genetic Medicine, Hokkaido University Faculty of Medicine, Sapporo, Japan
- *Correspondence: Ari Hashimoto, ; Shigeru Hashimoto,
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A Paradoxical Role for Regulatory T Cells in the Tumor Microenvironment of Pancreatic Cancer. Cancers (Basel) 2022; 14:cancers14163862. [PMID: 36010856 PMCID: PMC9405872 DOI: 10.3390/cancers14163862] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Revised: 07/18/2022] [Accepted: 08/05/2022] [Indexed: 11/17/2022] Open
Abstract
Simple Summary Pancreatic cancer is one of the most lethal cancer types and its high refractoriness to therapies, including immunotherapy, has often been associated with the predominantly immune suppressive tumor microenvironment that characterizes pancreatic tumors. Regulatory T cells (Tregs) are generally considered as drivers of immune suppression in cancers. However, an increasing number of reports suggest a paradoxical association between tumor infiltration by Tregs and improved patient prognosis, in particular in gastrointestinal cancers. Here we show that Treg infiltration in pancreatic ductal adenocarcinomas (PDAC) is associated with better overall survival of patients. Abstract Pancreatic ductal adenocarcinoma (PDAC) is considered to be a poorly immunogenic cancer type that combines a low mutation burden with a strong immunosuppressive tumor microenvironment. Regulatory T cells (Tregs) are major drivers of immune suppression but their prognostic role, particularly in gastrointestinal malignancies, remains controversial. Lymphocytic infiltration in 122 PDAC samples was assessed by multispectral immunofluorescence with anti-Keratin, -CD3, -CD8, -FOXP3 and -CD163 antibodies. Differential infiltration by Tregs was analyzed in the context of transcriptomic profiles that were available for 65 tumors. High infiltration of CD3+CD8− (mainly CD4+) T cells and, especially, of the subset expressing FOXP3 (Tregs) was associated with improved patient survival, whilst cytotoxic CD3+CD8+ T cell infiltration did not have an impact on overall survival. Transcriptomic analysis revealed three signatures in PDAC tumors comprising of epithelial-mesenchymal transition (EMT)/stromal, metabolic, and secretory/pancreatic signature. However, none of these signatures explained differences in Treg infiltration. We show that Tregs associate with improved overall survival in PDAC patients. This effect was independent of cytotoxic T cell infiltration and the transcriptomic profiles of their respective tumors. These findings provide a new layer of complexity in the study of PDAC tumor microenvironment that must be considered when developing immunotherapeutic interventions for this disease.
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Loening F, Kleinwort A, Partecke LI, Schulze T, Menges P. Visceral Surgery Profoundly Affects the Cellular and Humoral Components of the Anti-Tumour Immune Response in a Murine Pancreatic Adenocarcinoma Model. Cancers (Basel) 2022; 14:cancers14163850. [PMID: 36010845 PMCID: PMC9406220 DOI: 10.3390/cancers14163850] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 08/02/2022] [Accepted: 08/05/2022] [Indexed: 11/16/2022] Open
Abstract
Simple Summary Surgery is a fundamental part of the multimodal therapy concepts in oncological patients, especially in the early stage of pancreas tumour. There are numerous studies on the impact of primary tumour resection on the immune status, but to our knowledge, the impact of tumour-unrelated surgery on the anti-tumour immune response to the primary tumour it is not yet understood. Therefore, we used a murine model combining an orthotopically implanted adenocarcinoma of the pancreas and the model of surgically-induced immune dysfunction to assess the impact of postoperative immunosuppression on the growth of the primary tumour, on mortality and on the most important immune cell compartments in tumour defence. This knowledge might contribute to a basic understanding of the interaction of the primary tumour and the immune system and could guide new approaches to therapeutic strategies. Abstract (1) Background: Surgery is the most important element of multimodal treatment concepts in oncological patients, especially in the early stages of pancreatic tumours. While the influence of primary tumour resection on the immune status was analysed in several studies, the impact of tumour-unrelated visceral surgery on the tumour-bearing organism and on the primary tumour itself is not yet fully understood. (2) Methods: We combined a murine model of orthotopically implanted adenocarcinoma of the pancreas with the model of surgically-induced immune dysfunction (SID). Mortality and general condition including body weight were observed over a period of 28 days. Tumour growth was analysed by MRI scans on days 8 and 27 following tumour implantation. On day 28, the immune cell populations in the blood and spleen as well as the serum cytokines were quantified. (3) Results: SID results in a significant deterioration of the general condition and a reduced increase in the body weight of tumour-bearing mice compared to the control groups, while mortality and tumour growth rate were not influenced. The numbers of spleen macrophages and neutrophils were increased in tumour-bearing animals following SID. Furthermore, both macrophage and neutrophil levels were increased in the peripheral blood. (4) Conclusions: The presented results might contribute to the basic understanding of the interaction of tumour and immune system and could contribute to new approaches to immunotherapeutic strategies.
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Affiliation(s)
- Friederike Loening
- Division of General Surgery, Visceral, Thoracic and Vascular Surgery, Department of Surgery, University Medicine Greifswald, 17491 Greifswald, Germany
| | - Annabel Kleinwort
- Division of General Surgery, Visceral, Thoracic and Vascular Surgery, Department of Surgery, University Medicine Greifswald, 17491 Greifswald, Germany
| | - Lars Ivo Partecke
- Department of General, Visceral and Thoracic Surgery, Helios Clinic Schleswig, 24837 Schleswig, Germany
| | - Tobias Schulze
- Division of General Surgery, Visceral, Thoracic and Vascular Surgery, Department of Surgery, University Medicine Greifswald, 17491 Greifswald, Germany
| | - Pia Menges
- Division of General Surgery, Visceral, Thoracic and Vascular Surgery, Department of Surgery, University Medicine Greifswald, 17491 Greifswald, Germany
- Correspondence:
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Zhang J, Li R, Huang S. The immunoregulation effect of tumor microenvironment in pancreatic ductal adenocarcinoma. Front Oncol 2022; 12:951019. [PMID: 35965504 PMCID: PMC9365986 DOI: 10.3389/fonc.2022.951019] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Accepted: 07/04/2022] [Indexed: 11/25/2022] Open
Abstract
Pancreatic cancer has the seventh highest death rate of all cancers. The absence of any serious symptoms, coupled with a lack of early prognostic and diagnostic markers, makes the disease untreatable in most cases. This leads to a delay in diagnosis and the disease progresses so there is no cure. Only about 20% of cases are diagnosed early. Surgical removal is the preferred treatment for cancer, but chemotherapy is standard for advanced cancer, although patients can eventually develop drug resistance and serious side effects. Chemoresistance is multifactorial because of the interaction among pancreatic cancer cells, cancer stem cells, and the tumor microenvironment (TME). Nevertheless, more pancreatic cancer patients will benefit from precision treatment and targeted drugs. This review focuses on the immune-related components of TME and the interactions between tumor cells and TME during the development and progression of pancreatic cancer, including immunosuppression, tumor dormancy and escape. Finally, we discussed a variety of immune components-oriented immunotargeting drugs in TME from a clinical perspective.
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Affiliation(s)
| | - Renfeng Li
- The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Shuai Huang
- The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
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Smith C, Zheng W, Dong J, Wang Y, Lai J, Liu X, Yin F. Tumor microenvironment in pancreatic ductal adenocarcinoma: Implications in immunotherapy. World J Gastroenterol 2022; 28:3297-3313. [PMID: 36158269 PMCID: PMC9346457 DOI: 10.3748/wjg.v28.i27.3297] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Revised: 04/22/2022] [Accepted: 06/19/2022] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma is one of the most aggressive and lethal cancers. Surgical resection is the only curable treatment option, but it is available for only a small fraction of patients at the time of diagnosis. With current therapeutic regimens, the average 5-year survival rate is less than 10% in pancreatic cancer patients. Immunotherapy has emerged as one of the most promising treatment options for multiple solid tumors of advanced stage. However, its clinical efficacy is suboptimal in most clinical trials on pancreatic cancer. Current studies have suggested that the tumor microenvironment is likely the underlying barrier affecting immunotherapy drug efficacy in pancreatic cancer. In this review, we discuss the role of the tumor microenvironment in pancreatic cancer and the latest advances in immunotherapy on pancreatic cancer.
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Affiliation(s)
- Caitlyn Smith
- Department of Pathology and Anatomical Sciences, University of Missouri School of Medicine, Columbia, MO 65212, United States
| | - Wei Zheng
- Department of Pathology, Emory University School of Medicine, Atlanta, GA 30322, United States
| | - Jixin Dong
- Eppley Institute for Research in Cancer and Allied Diseases, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Yaohong Wang
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, United States
| | - Jinping Lai
- Department of Pathology and Laboratory Medicine, Kaiser Permanente Sacramento Medical Center, Sacramento, CA 95825, United States
| | - Xiuli Liu
- Department of Pathology and Immunology, Washington University, St. Louis, MO 63110, United States
| | - Feng Yin
- Department of Pathology and Anatomical Sciences, University of Missouri, Columbia, MO 65212, United States
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Lim CY, Chang JH, Lee WS, Kim J, Park IY. CD40 Agonists Alter the Pancreatic Cancer Microenvironment by Shifting the Macrophage Phenotype toward M1 and Suppress Human Pancreatic Cancer in Organotypic Slice Cultures. Gut Liver 2022; 16:645-659. [PMID: 34933280 PMCID: PMC9289829 DOI: 10.5009/gnl210311] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 08/24/2021] [Accepted: 09/03/2021] [Indexed: 11/04/2022] Open
Abstract
Background/Aims CD40 agonists are thought to generate antitumor effects on pancreatic cancer via macrophages and T cells. We aimed to investigate the role of CD40 agonists in the differentiation of macrophages and treatment of human pancreatic adenocarcinoma. Methods Immunohistochemistry was performed on paraffin-embedded surgical blocks from patients with pancreatic cancers to evaluate macrophage phenotypes and their relationship with survival. The effects of CD40 agonists on macrophage phenotypes and human pancreatic cancer were evaluated utilizing cell cocultures and organotypic slice cultures. Results CD163+ (predominant in M2 macrophages) and FOXP3+ (predominant in regulatory T cells) expression levels in the tumors were significantly lower in patients with stage IB pancreatic cancer than in those with stage II or III disease (p=0.002 and p=0.003, respectively). Patients with high CD163+ expression had shorter overall survival than those with low CD163+ expression (p=0.002). In vitro treatment of THP-1 macrophages with a CD40 agonist led to an increase in HLA-DR+ (predominant in M1 macrophages) and a decrease in CD163+ expression in THP-1 cells. Cell cocultures showed that CD40 agonists facilitate the suppression of PANC-1 human pancreatic cancer cells by THP-1 macrophages. Organotypic slice cultures showed that CD40 agonists alter the pancreatic cancer microenvironment by shifting the macrophage phenotype toward M1 (increase HLA-DR+ and decrease CD163+ expression), decreasing the abundance of regulatory T cells, and increasing tumor cell apoptosis. Conclusions CD163 is related to advanced human pancreatic cancer stages and shorter overall survival. CD40 agonists alter macrophage phenotype polarization to favor the M1 phenotype and suppress human pancreatic cancer.
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Affiliation(s)
- Chae Yoon Lim
- Institute of Clinical Medicine Research, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jae Hyuck Chang
- Departments of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Won Sun Lee
- Institute of Clinical Medicine Research, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jeana Kim
- Departments of Hospital Pathology, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Il Young Park
- Departments of Surgery, College of Medicine, The Catholic University of Korea, Seoul, Korea
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Petersson A, Andersson N, Hau SO, Eberhard J, Karlsson J, Chattopadhyay S, Valind A, Elebro J, Nodin B, Leandersson K, Gisselsson D, Jirström K. Branching Copy-Number Evolution and Parallel Immune Profiles across the Regional Tumor Space of Resected Pancreatic Cancer. Mol Cancer Res 2022; 20:749-761. [PMID: 35149544 PMCID: PMC9381114 DOI: 10.1158/1541-7786.mcr-21-0986] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 01/05/2022] [Accepted: 02/04/2022] [Indexed: 01/07/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal disease. The only option for curative treatment is resection of the tumor followed by standard adjuvant chemotherapy. Yet, early relapse due to chemoresistance is almost inevitable. Herein, we delineated the genetic intratumor heterogeneity in resected PDAC, with the aim to identify evolutionary patterns that may be associated with overall survival (OS) following treatment with curative intent. Potential relationships with the adjacent immune microenvironment were also examined. The genetic and immune landscapes of the regional tumor space were analyzed in nine patients with resected PDAC. Targeted deep sequencing and genome wide SNP array were followed by clonal deconvolution and phylogenetic analysis. A mathematical complexity score was developed to calculate the network extent of each phylogeny. Spatial variation in abundancy and tumor nest infiltration of immune cells was analyzed by double IHC staining. Copy-number heterogeneity was denoted as the major contributing factor to the branching architectures of the produced phylogenetic trees. Increased tree complexity was significantly inversely associated with OS, and larger regional maximum aberrations (higher treetops) were associated with increased PD-L1 expression on tumor cells. Contrastingly, an FREM1 gene amplification, found in one patient, coincided with a particularly vigorous immune response. Findings from this limited case series suggest that complex evolutionary patterns may be associated with a shorter survival in surgically treated patients with PDAC. Some hypothesis-generating associations with the surrounding immune microenvironment were also detected. IMPLICATIONS Evolutionary copy-number patterns may be associated with survival in patients with resected PDAC.
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Affiliation(s)
- Alexandra Petersson
- Division of Oncology and Therapeutic Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden
| | - Natalie Andersson
- Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden
| | - Sofie Olsson Hau
- Division of Oncology and Therapeutic Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden
| | - Jakob Eberhard
- Division of Oncology and Therapeutic Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden
| | - Jenny Karlsson
- Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden
| | - Subhayan Chattopadhyay
- Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden
| | - Anders Valind
- Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden
- Department of Pediatrics, Skåne University Hospital, Lund, Sweden
| | - Jacob Elebro
- Division of Oncology and Therapeutic Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden
| | - Björn Nodin
- Division of Oncology and Therapeutic Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden
| | - Karin Leandersson
- Cancer Immunology, Department of Translational Medicine, Lund University, Malmö, Sweden
| | - David Gisselsson
- Division of Oncology and Therapeutic Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden
- Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden
| | - Karin Jirström
- Division of Oncology and Therapeutic Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden
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An emerging role of KRAS in biogenesis, cargo sorting and uptake of cancer-derived extracellular vesicles. Future Med Chem 2022; 14:827-845. [PMID: 35502655 DOI: 10.4155/fmc-2021-0332] [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: 11/17/2022] Open
Abstract
Extracellular vesicles (EVs) are nanovesicles secreted for intercellular communication with endosomal network regulating secretion of small EVs (or exosomes) that play roles in cancer progression. As an essential oncoprotein, Kirsten rat sarcoma virus (KRAS) is tightly regulated by its endosomal trafficking for membrane attachment. However, the crosstalk between KRAS and EVs has been scarcely discussed despite its endocytic association. An overview of the oncogenic role of KRAS focusing on its correlation with cancer-associated EVs should provide important clues for disease prognosis and inspire novel therapeutic approaches for treating KRAS mutant cancers. Therefore, this review summarizes the relevant studies that provide substantial evidence linking KRAS mutation to EVs and discusses the oncogenic implication from the aspects of biogenesis, cargo sorting, and release and uptake of the EVs.
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Chen Q, Wang Q, Wang Y, Chu Y, Luo Y, You H, Su B, Li C, Guo Q, Sun T, Jiang C. Penetrating Micelle for Reversing Immunosuppression and Drug Resistance in Pancreatic Cancer Treatment. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2022; 18:e2107712. [PMID: 35285149 DOI: 10.1002/smll.202107712] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 02/11/2022] [Indexed: 06/14/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is on of the most lethal malignant tumors with relatively poor prognosis, characterized with insufficient drug penetration, low immune response and obvious drug resistances. The therapeutic inefficiency is multifactorially related to its specific tumor microenvironment (TME), which is representatively featured as rich stroma and immunosuppression. In this work, a versatile drug delivery system is developed that can coencapsulate two prodrugs modified from gemcitabine (GEM) and a signal transducer and activator of transcription 3 (STAT3) inhibitor (HJC0152), and the gradient pH variation is further sensed in the TME of PDAC to achieve a higher penetration by reversing its surficial charges. The escorted prodrugs can release GEM intracellularly, and respond to the hypoxic condition to yield the parental STAT3 inhibitor HJC0152, respectively. By inhibiting STAT3, the tumor immunosuppression microenvironment can be re-educated through the reversion of M2-like tumor associated macrophages (M2-TAMs), recruitment of cytotoxic T lymphocytes and downregulation of regulatory T cells (Treg s). Furthermore, cytidine deaminase (CDA) and α-smooth muscle actin (α-SMA) expression can be downregulated, plus the lipid modification of GEM, the drug resistance of GEM can be greatly relieved. Based on the above design, a synergetic therapeutic efficacy in PDAC treatment can be achieved to provide more opportunity for clinical applications.
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Affiliation(s)
- Qinjun Chen
- Key Laboratory of Smart Drug Delivery (Ministry of Education), Minhang Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Department of Pharmaceutics, School of Pharmacy, Research Center on Aging and Medicine, Fudan University, Shanghai, 201203, P. R. China
| | - Qingbing Wang
- Department of Interventional Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, P. R. China
| | - Yu Wang
- Key Laboratory of Smart Drug Delivery (Ministry of Education), Minhang Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Department of Pharmaceutics, School of Pharmacy, Research Center on Aging and Medicine, Fudan University, Shanghai, 201203, P. R. China
| | - Yongchao Chu
- Key Laboratory of Smart Drug Delivery (Ministry of Education), Minhang Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Department of Pharmaceutics, School of Pharmacy, Research Center on Aging and Medicine, Fudan University, Shanghai, 201203, P. R. China
| | - Yifan Luo
- Key Laboratory of Smart Drug Delivery (Ministry of Education), Minhang Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Department of Pharmaceutics, School of Pharmacy, Research Center on Aging and Medicine, Fudan University, Shanghai, 201203, P. R. China
| | - Haoyu You
- Key Laboratory of Smart Drug Delivery (Ministry of Education), Minhang Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Department of Pharmaceutics, School of Pharmacy, Research Center on Aging and Medicine, Fudan University, Shanghai, 201203, P. R. China
| | - Boyu Su
- Key Laboratory of Smart Drug Delivery (Ministry of Education), Minhang Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Department of Pharmaceutics, School of Pharmacy, Research Center on Aging and Medicine, Fudan University, Shanghai, 201203, P. R. China
| | - Chao Li
- Key Laboratory of Smart Drug Delivery (Ministry of Education), Minhang Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Department of Pharmaceutics, School of Pharmacy, Research Center on Aging and Medicine, Fudan University, Shanghai, 201203, P. R. China
| | - Qin Guo
- Key Laboratory of Smart Drug Delivery (Ministry of Education), Minhang Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Department of Pharmaceutics, School of Pharmacy, Research Center on Aging and Medicine, Fudan University, Shanghai, 201203, P. R. China
| | - Tao Sun
- Key Laboratory of Smart Drug Delivery (Ministry of Education), Minhang Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Department of Pharmaceutics, School of Pharmacy, Research Center on Aging and Medicine, Fudan University, Shanghai, 201203, P. R. China
| | - Chen Jiang
- Key Laboratory of Smart Drug Delivery (Ministry of Education), Minhang Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Department of Pharmaceutics, School of Pharmacy, Research Center on Aging and Medicine, Fudan University, Shanghai, 201203, P. R. China
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Zhang Y, Brekken RA. Direct and indirect regulation of the tumor immune microenvironment by VEGF. J Leukoc Biol 2022; 111:1269-1286. [DOI: 10.1002/jlb.5ru0222-082r] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 04/06/2022] [Accepted: 04/07/2022] [Indexed: 12/19/2022] Open
Affiliation(s)
- Yuqing Zhang
- Hamon Center for Therapeutic Oncology Research UT Southwestern Medical Center Dallas Texas USA
- Department of Surgery UT Southwestern Medical Center Dallas Texas USA
- Cancer Biology Graduate Program UT Southwestern Medical Center Dallas Texas USA
- Current affiliation: Department of Medical Oncology Dana‐Farber Cancer Institute Boston Massachusetts USA
| | - Rolf A. Brekken
- Hamon Center for Therapeutic Oncology Research UT Southwestern Medical Center Dallas Texas USA
- Department of Surgery UT Southwestern Medical Center Dallas Texas USA
- Cancer Biology Graduate Program UT Southwestern Medical Center Dallas Texas USA
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Maurer MF, Lewis KE, Kuijper JL, Ardourel D, Gudgeon CJ, Chandrasekaran S, Mudri SL, Kleist KN, Navas C, Wolfson MF, Rixon MW, Swanson R, Dillon SR, Levin SD, Kimbung YR, Akutsu M, Logan DT, Walse B, Swiderek KM, Peng SL. The engineered CD80 variant fusion therapeutic davoceticept combines checkpoint antagonism with conditional CD28 costimulation for anti-tumor immunity. Nat Commun 2022; 13:1790. [PMID: 35379805 PMCID: PMC8980021 DOI: 10.1038/s41467-022-29286-5] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Accepted: 03/09/2022] [Indexed: 11/09/2022] Open
Abstract
AbstractDespite the recent clinical success of T cell checkpoint inhibition targeting the CTLA-4 and PD-1 pathways, many patients either fail to achieve objective responses or they develop resistance to therapy. In some cases, poor responses to checkpoint blockade have been linked to suboptimal CD28 costimulation and the inability to generate and maintain a productive adaptive anti-tumor immune response. To address this, here we utilize directed evolution to engineer a CD80 IgV domain with increased PD-L1 affinity and fuse this to an immunoglobulin Fc domain, creating a therapeutic (ALPN-202, davoceticept) capable of providing CD28 costimulation in a PD-L1-dependent fashion while also antagonizing PD-1 - PD-L1 and CTLA-4–CD80/CD86 interactions. We demonstrate that by combining CD28 costimulation and dual checkpoint inhibition, ALPN-202 enhances T cell activation and anti-tumor efficacy in cell-based assays and mouse tumor models more potently than checkpoint blockade alone and thus has the potential to generate potent, clinically meaningful anti-tumor immunity in humans.
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Singla RK, Behzad S, Khan J, Tsagkaris C, Gautam RK, Goyal R, Chopra H, Shen B. Natural Kinase Inhibitors for the Treatment and Management of Endometrial/Uterine Cancer: Preclinical to Clinical Studies. Front Pharmacol 2022; 13:801733. [PMID: 35264951 PMCID: PMC8899191 DOI: 10.3389/fphar.2022.801733] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Accepted: 01/17/2022] [Indexed: 02/05/2023] Open
Abstract
Endometrial cancer (EC) is the sixth most prevalent type of cancer among women. Kinases, enzymes mediating the transfer of adenosine triphosphate (ATP) in several signaling pathways, play a significant role in carcinogenesis and cancer cells’ survival and proliferation. Cyclin-dependent kinases (CDKs) are involved in EC pathogenesis; therefore, CDK inhibitors (CDKin) have a noteworthy therapeutic potential in this type of cancer, particularly in EC type 1. Natural compounds have been used for decades in the treatment of cancer serving as a source of anticancer bioactive molecules. Many phenolic and non-phenolic natural compounds covering flavonoids, stilbenoids, coumarins, biphenyl compounds, alkaloids, glycosides, terpenes, and terpenoids have shown moderate to high effectiveness against CDKin-mediated carcinogenic signaling pathways (PI3K, ERK1/2, Akt, ATM, mTOR, TP53). Pharmaceutical regimens based on two natural compounds, trabectedin and ixabepilone, have been investigated in humans showing short and midterm efficacy as second-line treatments in phase II clinical trials. The purpose of this review is twofold: the authors first provide an overview of the involvement of kinases and kinase inhibitors in the pathogenesis and treatment of EC and then discuss the existing evidence about natural products’ derived kinase inhibitors in the management of the disease and outline relevant future research.
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Affiliation(s)
- Rajeev K Singla
- Institutes for Systems Genetics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China.,IGlobal Research and Publishing Foundation, New Delhi, India
| | - Sahar Behzad
- Evidence-based Phytotherapy and Complementary Medicine Research Center, Alborz University of Medical Sciences, Karaj, Iran.,Department of Pharmacognosy, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Johra Khan
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Al Majmaah, Saudi Arabia.,Health and Basic Sciences Research Center, Majmaah University, Majmaah, Saudi Arabia
| | | | - Rupesh K Gautam
- Department of Pharmacology, MM School of Pharmacy, MM University, Ambala, India
| | - Rajat Goyal
- Department of Pharmacology, MM School of Pharmacy, MM University, Ambala, India
| | | | - Bairong Shen
- Institutes for Systems Genetics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
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Analysis of Stemness and Prognosis of Subtypes in Breast Cancer Using the Transcriptome Sequencing Data. JOURNAL OF ONCOLOGY 2022; 2022:5694033. [PMID: 35310908 PMCID: PMC8926471 DOI: 10.1155/2022/5694033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Accepted: 02/02/2022] [Indexed: 12/24/2022]
Abstract
The stem characteristics of tumor cells have been proposed in theory very early, and we can use the signature of gene expression to speculate the stemness of tumor cells. However, systematic studies on the stemness of breast cancer as well as breast cancer subtypes, and the relationship between stemness and metastasis and prognosis, are still lacking. In the present research, using the transcriptome data of patients with breast cancer in the TCGA database, a stemness prediction model was utilized to derive the stemness of the patients’ tumors. We compared the stemness values among different subtypes and the differences with metastasis. COX regression was employed to evaluate the correlation between stemness value as well as prognosis. Using the Lasso-penalized Cox regression machine learning model, we obtained the gene signature of the basal subtype that is related to stemness and can also predict the prognosis of the patient. Patients can be stratified into two groups of high and low stemness, corresponding to good and poor prognosis. Based on further prediction of tumor infiltration by CIBERSORT and prediction of drug response by a connectivity map, we found that the difference in stemness between these two groups is associated with the activation of tumor-killing immune cells and drug response. Our findings can promote the understanding and research of subtypes of basal breast cancer and provide corresponding molecular markers for clinical detection and therapy.
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The Hodgkin Lymphoma Immune Microenvironment: Turning Bad News into Good. Cancers (Basel) 2022; 14:cancers14051360. [PMID: 35267668 PMCID: PMC8909875 DOI: 10.3390/cancers14051360] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 02/09/2022] [Accepted: 03/02/2022] [Indexed: 02/05/2023] Open
Abstract
The classic Hodgkin lymphoma (cHL) tumor microenvironment (TME) is by far the most abundant component of tumors and is responsible for most of their biological and clinical characteristics. Recent advances in our knowledge of these networks in cellular interactions allow us to understand that the neoplastic Hodgkin and Reed Sternberg (HRS) cells, although they are in the minority, are the main architects of this dysregulated immune milieu. Here, we review the major changes that have happened in recent years: from TME as a helpless bystander, reflecting an ineffective immune response, to a dynamic tumor-promoting and immunosuppressive element. The HRS cells promote survival through interconnected intrinsic and extrinsic alterations, boosting pro-tumoral signaling pathways through genetic aberrations and autocrine growth signals, in parallel with abnormal cytokine secretion for the recruitment and selection of the best cell partners for this immunosuppressive TME. In turn, cHL is already proving to be the perfect model with which to address an immune checkpoint blockade. Preliminary data demonstrate the utility of druggable key signaling pathways in this ensemble, such as JAK-STAT, NF-κB, and others. In addition, myriad biomarkers predicting a response await validation by new in situ multiplex analytical methods, single-cell gene expression, and other techniques. Together, these components will define the functional phenotypes with which we will elucidate the molecular pathogenesis of the disease and improve the survival of patients who are refractory to conventional therapies.
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Bachy S, Wu Z, Gamradt P, Thierry K, Milani P, Chlasta J, Hennino A. βig-h3-structured collagen alters macrophage phenotype and function in pancreatic cancer. iScience 2022; 25:103758. [PMID: 35146384 PMCID: PMC8816720 DOI: 10.1016/j.isci.2022.103758] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 10/27/2021] [Accepted: 01/07/2022] [Indexed: 12/02/2022] Open
Abstract
Macrophages play an important role in immune and matrix regulation during pancreatic adenocarcinoma (PDAC). Collagen deposition massively contributes to the physical and functional changes of the tissue during pathogenesis. We investigated the impact of thick collagen fibers on the phenotype and function of macrophages. We recently demonstrated that the extracellular protein βig-h3/TGFβi (Transforming growth factor-β-induced protein) plays an important role in modulating the stiffness of the pancreatic stroma. By using atomic force microscopy, we show that βig-h3 binds to type I collagen and establishes thicker fibers. Macrophages cultured on βig-h3-structured collagen layers display a different morphology and a pro-tumoral M2 phenotype and function compared to those cultured on non-structured collagen layers. In vivo injection of those instructed CD206+CD163+ macrophages was able to suppress T cell responses. These results reveal for the first time that the collagen structure impacts the phenotype and function of macrophages by potentiating their immunosuppressive features.
Atomic force microscopy of βig-h3-structured collagen In vitro and in vivo macrophage education on structured collagen In vitro macrophage phenotype imprinting is stable in vivo
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Affiliation(s)
- Sophie Bachy
- Cancer Research Center of Lyon, UMR INSERM1052, CNRS5286, 69373 Lyon, France.,Université Lyon 1, 69000 Lyon, France.,Centre Léon Bérard, 69008 Lyon, France
| | - Zhichong Wu
- Cancer Research Center of Lyon, UMR INSERM1052, CNRS5286, 69373 Lyon, France.,Université Lyon 1, 69000 Lyon, France.,Centre Léon Bérard, 69008 Lyon, France
| | - Pia Gamradt
- Cancer Research Center of Lyon, UMR INSERM1052, CNRS5286, 69373 Lyon, France.,Université Lyon 1, 69000 Lyon, France.,Centre Léon Bérard, 69008 Lyon, France
| | - Kevin Thierry
- Cancer Research Center of Lyon, UMR INSERM1052, CNRS5286, 69373 Lyon, France.,Université Lyon 1, 69000 Lyon, France.,Centre Léon Bérard, 69008 Lyon, France
| | | | | | - Ana Hennino
- Cancer Research Center of Lyon, UMR INSERM1052, CNRS5286, 69373 Lyon, France.,Université Lyon 1, 69000 Lyon, France.,Centre Léon Bérard, 69008 Lyon, France
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Davis JM, Cheng B, Drake MM, Yu Q, Yang B, Li J, Liu C, Younes M, Zhao X, Bailey JM, Shen Q, Ko TC, Cao Y. Pancreatic stromal Gremlin 1 expression during pancreatic tumorigenesis. Genes Dis 2022; 9:108-115. [PMID: 35005111 PMCID: PMC8720668 DOI: 10.1016/j.gendis.2020.05.001] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Revised: 04/07/2020] [Accepted: 05/08/2020] [Indexed: 12/28/2022] Open
Abstract
Chronic pancreatitis (CP) is a major risk factor of pancreatic ductal adenocarcinoma (PDAC). How CP promotes pancreatic oncogenesis remains unclear. A characteristic feature of PDAC is its prominent desmoplasia in the tumor microenvironment, composed of activated fibroblasts and macrophages. Macrophages can be characterized as M1 or M2, with tumor-inhibiting or -promoting functions, respectively. We reported that Gremlin 1 (GREM1), a key pro-fibrogenic factor, is upregulated in the stroma of CP. The current study aimed to investigate the expression of GREM1 and correlation between GREM1 and macrophages within the pancreas during chronic inflammation and the development of PDAC. By mRNA in situ hybridization, we detected GREM1 mRNA expression within α-smooth muscle actin (SMA)-positive fibroblasts of the pancreatic stroma. These designated FibroblastsGrem1+ marginally increased from CP to pancreatic intraepithelial neoplasia (PanIN) and PDAC. Within PDAC, FibroblastsGrem1+ increased with higher pathological tumor stages and in a majority of PDAC subtypes screened. Additionally, FibroblastsGrem1+ positively correlated with total macrophages (MacCD68+) and M2 macrophages (M2CD163+) in PDAC. To begin exploring potential molecular links between FibroblastsGrem1+ and macrophages in PDAC, we examined the expression of macrophage migration inhibitory factor (MIF), an endogenous counteracting molecule of GREM1 and an M1 macrophage promoting factor. By IHC staining of MIF, we found MIF to be expressed by tumor cells, positively correlated with GREM1; by IHC co-staining, we found MIF to be negatively correlated with M2CD163+ expression. Our findings suggest that GREM1 expression by activated fibroblasts may promote PDAC development, and GREM1/MIF may play an important role in macrophage phenotype.
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Affiliation(s)
- Joy M. Davis
- Department of Surgery, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Binglu Cheng
- Department of Surgery, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Madeline M. Drake
- Department of Surgery, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Qiang Yu
- Department of Surgery, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Baibing Yang
- Department of Surgery, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Jing Li
- Department of Surgery, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Chunhui Liu
- Department of Surgery, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Mamoun Younes
- Department of Pathology & Laboratory Medicine, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Xiurong Zhao
- Department of Neurology, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Jennifer M. Bailey
- Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Qiang Shen
- Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA
| | - Tien C. Ko
- Department of Surgery, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Yanna Cao
- Department of Surgery, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
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TNFSF9 promotes metastasis of pancreatic cancer by regulating M2 polarization of macrophages through Src/FAK/p-Akt/IL-1β signaling. Int Immunopharmacol 2021; 102:108429. [PMID: 34906856 DOI: 10.1016/j.intimp.2021.108429] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Revised: 11/29/2021] [Accepted: 11/30/2021] [Indexed: 02/07/2023]
Abstract
The effect of tumor necrosis factor superfamily member 9 (TNFSF9) on the metastasis of pancreatic cancer (PC) and the underlying mechanism remain unclear. We studied the expression of TNFSF9 in pancreatic cancer and its relationship with immune cells. We further explored the effect of TNFSF9 on pancreatic cancer metastasis by inducing macrophage polarization, and evaluated the expression of Src/FAK/p-Akt/IL-1β signals in macrophages after knocking down TNFSF9. The data shows that TNFSF9 expression is elevated in pancreatic cancer and is related to the poor prognosis of patients with pancreatic cancer. In addition, TNFSF9 may induce the M2 polarization of macrophages through Src/FAK/p-Akt/IL-1β signals, thereby promoting the migration of pancreatic cancer cells. In conclusion, our data reveals that TNFSF9 may become a predictive biomarker of pancreatic cancer and provides a new intervention target for the immunotherapy of pancreatic cancer.
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Nanomedicine in Pancreatic Cancer: Current Status and Future Opportunities for Overcoming Therapy Resistance. Cancers (Basel) 2021; 13:cancers13246175. [PMID: 34944794 PMCID: PMC8699181 DOI: 10.3390/cancers13246175] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 11/12/2021] [Accepted: 11/16/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Despite access to a vast arsenal of anticancer agents, many fail to realise their full therapeutic potential in clinical practice. One key determinant of this is the evolution of multifaceted resistance mechanisms within the tumour that may either pre-exist or develop during the course of therapy. This is particularly evident in pancreatic cancer, where limited responses to treatment underlie dismal survival rates, highlighting the urgent need for new therapeutic approaches. Here, we discuss the major features of pancreatic tumours that contribute to therapy resistance, and how they may be alleviated through exploitation of the mounting and exciting promise of nanomedicines; a unique collection of nanoscale platforms with tunable and multifunctional capabilities that have already elicited a widespread impact on cancer management. Abstract The development of drug resistance remains one of the greatest clinical oncology challenges that can radically dampen the prospect of achieving complete and durable tumour control. Efforts to mitigate drug resistance are therefore of utmost importance, and nanotechnology is rapidly emerging for its potential to overcome such issues. Studies have showcased the ability of nanomedicines to bypass drug efflux pumps, counteract immune suppression, serve as radioenhancers, correct metabolic disturbances and elicit numerous other effects that collectively alleviate various mechanisms of tumour resistance. Much of this progress can be attributed to the remarkable benefits that nanoparticles offer as drug delivery vehicles, such as improvements in pharmacokinetics, protection against degradation and spatiotemporally controlled release kinetics. These attributes provide scope for precision targeting of drugs to tumours that can enhance sensitivity to treatment and have formed the basis for the successful clinical translation of multiple nanoformulations to date. In this review, we focus on the longstanding reputation of pancreatic cancer as one of the most difficult-to-treat malignancies where resistance plays a dominant role in therapy failure. We outline the mechanisms that contribute to the treatment-refractory nature of these tumours, and how they may be effectively addressed by harnessing the unique capabilities of nanomedicines. Moreover, we include a brief perspective on the likely future direction of nanotechnology in pancreatic cancer, discussing how efforts to develop multidrug formulations will guide the field further towards a therapeutic solution for these highly intractable tumours.
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Malinova A, Veghini L, Real FX, Corbo V. Cell Lineage Infidelity in PDAC Progression and Therapy Resistance. Front Cell Dev Biol 2021; 9:795251. [PMID: 34926472 PMCID: PMC8675127 DOI: 10.3389/fcell.2021.795251] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Accepted: 11/15/2021] [Indexed: 12/23/2022] Open
Abstract
Infidelity to cell fate occurs when differentiated cells lose their original identity and either revert to a more multipotent state or transdifferentiate into a different cell type, either within the same embryonic lineage or in an entirely different one. Whilst in certain circumstances, such as in wound repair, this process is beneficial, it can be hijacked by cancer cells to drive disease initiation and progression. Cell phenotype switching has been shown to also serve as a mechanism of drug resistance in some epithelial cancers. In pancreatic ductal adenocarcinoma (PDAC), the role of lineage infidelity and phenotype switching is still unclear. Two consensus molecular subtypes of PDAC have been proposed that mainly reflect the existence of cell lineages with different degrees of fidelity to pancreatic endodermal precursors. Indeed, the classical subtype of PDAC is characterised by the expression of endodermal lineage specifying transcription factors, while the more aggressive basal-like/squamous subtype is defined by epigenetic downregulation of endodermal genes and alterations in chromatin modifiers. Here, we summarise the current knowledge of mechanisms (genetic and epigenetic) of cell fate switching in PDAC and discuss how pancreatic organoids might help increase our understanding of both cell-intrinsic and cell-extrinsic factors governing lineage infidelity during the distinct phases of PDAC evolution.
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Affiliation(s)
- Antonia Malinova
- Department of Diagnostics and Public Health, University of Verona, Verona, Italy
| | - Lisa Veghini
- Department of Diagnostics and Public Health, University of Verona, Verona, Italy
| | - Francisco X. Real
- Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre, Madrid, Spain
- CIBERONC, Madrid, Spain
- Department de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain
| | - Vincenzo Corbo
- Department of Diagnostics and Public Health, University of Verona, Verona, Italy
- ARC-Net Research Centre, University of Verona, Verona, Italy
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Shin HC, Seo I, Jeong H, Byun SJ, Kim S, Bae SU, Kwon SY, Lee HW. Prognostic Impact of Tumor-Associated Macrophages on Long-Term Oncologic Outcomes in Colorectal Cancer. Life (Basel) 2021; 11:1240. [PMID: 34833118 PMCID: PMC8618174 DOI: 10.3390/life11111240] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 11/07/2021] [Accepted: 11/09/2021] [Indexed: 12/26/2022] Open
Abstract
This study evaluated the correlation between tumor-associated macrophages (TAMs) and long-term oncologic outcomes in colorectal cancer (CRC). We evaluated TAMs based on the expression of CD68, CD11c, and CD163 as optimal markers via immunohistochemistry in 148 patients with CRC who underwent surgical resection between September 1999 and August 2004. A high proportion of CD68-positive macrophages were associated with the occurrence of distant metastasis. A low proportion of CD11c-positive macrophages were associated with unfavorable overall survival (OS) and disease-free survival. CD11c-positive macrophages were found to act as independent prognostic factors for OS. An analysis of our long-term data indicated that TAMs are significantly associated with OS and prognosis in CRC.
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Affiliation(s)
- Hyeong Chan Shin
- Department of Pathology, Keimyung University School of Medicine, Dongsan Hospital, Daegu 42601, Korea; (H.C.S.); (H.J.); (S.Y.K.)
| | - Incheol Seo
- Department of Microbiology, Dongguk University College of Medicine, Gyeongju 38067, Korea;
| | - Hasong Jeong
- Department of Pathology, Keimyung University School of Medicine, Dongsan Hospital, Daegu 42601, Korea; (H.C.S.); (H.J.); (S.Y.K.)
| | - Sang Jun Byun
- Department of Radiation Oncology, Keimyung University School of Medicine, Dongsan Hospital, Daegu 42601, Korea;
| | - Shin Kim
- Department of Immunology, Keimyung University School of Medicine, Daegu 42601, Korea;
| | - Sung Uk Bae
- Department of Surgery, Keimyung University School of Medicine, Dongsan Hospital, Daegu 42601, Korea;
| | - Sun Young Kwon
- Department of Pathology, Keimyung University School of Medicine, Dongsan Hospital, Daegu 42601, Korea; (H.C.S.); (H.J.); (S.Y.K.)
| | - Hye Won Lee
- Department of Pathology, Keimyung University School of Medicine, Dongsan Hospital, Daegu 42601, Korea; (H.C.S.); (H.J.); (S.Y.K.)
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Ostios-Garcia L, Villamayor J, Garcia-Lorenzo E, Vinal D, Feliu J. Understanding the immune response and the current landscape of immunotherapy in pancreatic cancer. World J Gastroenterol 2021; 27:6775-6793. [PMID: 34790007 PMCID: PMC8567475 DOI: 10.3748/wjg.v27.i40.6775] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 06/28/2021] [Accepted: 09/19/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive tumor with high lethality. Even with surgery, radiotherapy, chemotherapy, and other locoregional or systemic therapies, the survival rates for PDAC are low and have not significantly changed in the past decades. The special characteristics of the PDAC's microenvironment and its complex immune escape mechanism need to be considered when designing novel therapeutic approaches in this disease. PDAC is characterized by chronic inflammation with a high rate of tumor-associated macrophages and myeloid-derived suppressor cells and a low rate of natural killer and effector T cells. The pancreatic microenvironment is a fibrotic, microvascularized stroma that isolates the tumor from systemic vascularization. Immunotherapy, a novel approach that has demonstrated effectiveness in certain solid tumors, has failed to show any practice-changing results in pancreatic cancer, with the exception of PDACs with mismatch repair deficiency and high tumor mutational burden, which show prolonged survival rates with immunotherapy. Currently, numerous clinical trials are attempting to assess the efficacy of immunotherapeutic strategies in PDAC, including immune checkpoint inhibitors, cancer vaccines, and adoptive cell transfer, alone or in combination with other immunotherapeutic agents, chemoradiotherapy, and other targeted therapies. A deep understanding of the immune response will help in the development of new therapeutic strategies leading to improved clinical outcomes for patients with PDAC.
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Affiliation(s)
- Lorena Ostios-Garcia
- Department of Oncology, La Paz University Hospital, IDIPAZ, CIBERONC, Cátedra UAM-AMGEN, Madrid 28046, Spain
| | - Julia Villamayor
- Department of Oncology, La Paz University Hospital, IDIPAZ, CIBERONC, Cátedra UAM-AMGEN, Madrid 28046, Spain
| | - Esther Garcia-Lorenzo
- Department of Oncology, La Paz University Hospital, IDIPAZ, CIBERONC, Cátedra UAM-AMGEN, Madrid 28046, Spain
| | - David Vinal
- Department of Oncology, La Paz University Hospital, IDIPAZ, CIBERONC, Cátedra UAM-AMGEN, Madrid 28046, Spain
| | - Jaime Feliu
- Department of Oncology, La Paz University Hospital, IDIPAZ, CIBERONC, Cátedra UAM-AMGEN, Madrid 28046, Spain
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