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Zhang W, Lu Y, Shen R, Wu Y, Liu C, Fang X, Zhang L, Liu B, Rong L. Inhibiting ceramide synthase 5 expression in microglia decreases neuroinflammation after spinal cord injury. Neural Regen Res 2025; 20:2955-2968. [PMID: 39610106 PMCID: PMC11826471 DOI: 10.4103/nrr.nrr-d-23-01933] [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: 11/26/2023] [Revised: 02/24/2024] [Accepted: 04/15/2024] [Indexed: 11/30/2024] Open
Abstract
JOURNAL/nrgr/04.03/01300535-202510000-00026/figure1/v/2024-11-26T163120Z/r/image-tiff Microglia, the resident monocyte of the central nervous system, play a crucial role in the response to spinal cord injury. However, the precise mechanism remains unclear. To investigate the molecular mechanisms by which microglia regulate the neuroinflammatory response to spinal cord injury, we performed single-cell RNA sequencing dataset analysis, focusing on changes in microglial subpopulations. We found that the MG1 subpopulation emerged in the acute/subacute phase of spinal cord injury and expressed genes related to cell pyroptosis, sphingomyelin metabolism, and neuroinflammation at high levels. Subsequently, we established a mouse model of contusive injury and performed intrathecal injection of siRNA and molecular inhibitors to validate the role of ceramide synthase 5 in the neuroinflammatory responses and pyroptosis after spinal cord injury. Finally, we established a PC12-BV2 cell co-culture system and found that ceramide synthase 5 and pyroptosis-associated proteins were highly expressed to induce the apoptosis of neuron cells. Inhibiting ceramide synthase 5 expression in a mouse model of spinal cord injury effectively reduced pyroptosis. Furthermore, ceramide synthase 5-induced pyroptosis was dependent on activation of the NLRP3 signaling pathway. Inhibiting ceramide synthase 5 expression in microglia in vivo reduced neuronal apoptosis and promoted recovery of neurological function. Pla2g7 formed a "bridge" between sphingolipid metabolism and ceramide synthase 5-mediated cell death by inhibiting the NLRP3 signaling pathway. Collectively, these findings suggest that inhibiting ceramide synthase 5 expression in microglia after spinal cord injury effectively suppressed microglial pyroptosis mediated by NLRP3, thereby exerting neuroprotective effects.
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Affiliation(s)
- Wei Zhang
- Department of Spine Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
- National Medical Products Administration (NMPA) Key Laboratory for Quality Research and Evaluation of Cell Products, Guangzhou, Guangdong Province, China
- Guangdong Provincial Center for Quality Control of Minimally Invasive Spine Surgery, Guangzhou, Guangdong Province, China
- Guangdong Provincial Center for Engineering and Technology Research of Minimally Invasive Spine Surgery, Guangzhou, Guangdong Province, China
| | - Yubao Lu
- Department of Spine Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
- National Medical Products Administration (NMPA) Key Laboratory for Quality Research and Evaluation of Cell Products, Guangzhou, Guangdong Province, China
- Guangdong Provincial Center for Quality Control of Minimally Invasive Spine Surgery, Guangzhou, Guangdong Province, China
- Guangdong Provincial Center for Engineering and Technology Research of Minimally Invasive Spine Surgery, Guangzhou, Guangdong Province, China
| | - Ruoqi Shen
- Department of Spine Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Yingjie Wu
- Department of Spine Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Chenrui Liu
- Department of Spine Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Xingxing Fang
- Department of Spine Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Liangming Zhang
- Department of Spine Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
- National Medical Products Administration (NMPA) Key Laboratory for Quality Research and Evaluation of Cell Products, Guangzhou, Guangdong Province, China
- Guangdong Provincial Center for Quality Control of Minimally Invasive Spine Surgery, Guangzhou, Guangdong Province, China
- Guangdong Provincial Center for Engineering and Technology Research of Minimally Invasive Spine Surgery, Guangzhou, Guangdong Province, China
| | - Bin Liu
- Department of Spine Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
- National Medical Products Administration (NMPA) Key Laboratory for Quality Research and Evaluation of Cell Products, Guangzhou, Guangdong Province, China
- Guangdong Provincial Center for Quality Control of Minimally Invasive Spine Surgery, Guangzhou, Guangdong Province, China
- Guangdong Provincial Center for Engineering and Technology Research of Minimally Invasive Spine Surgery, Guangzhou, Guangdong Province, China
| | - Limin Rong
- Department of Spine Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
- National Medical Products Administration (NMPA) Key Laboratory for Quality Research and Evaluation of Cell Products, Guangzhou, Guangdong Province, China
- Guangdong Provincial Center for Quality Control of Minimally Invasive Spine Surgery, Guangzhou, Guangdong Province, China
- Guangdong Provincial Center for Engineering and Technology Research of Minimally Invasive Spine Surgery, Guangzhou, Guangdong Province, China
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Mizobuchi H, Yamagishi J, Sanjoba C, Goto Y. Vertical transmission of Leishmania donovani with placental degeneration in the pregnant mouse model of visceral leishmaniasis. PLoS Negl Trop Dis 2025; 19:e0012650. [PMID: 40489555 DOI: 10.1371/journal.pntd.0012650] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Revised: 06/17/2025] [Accepted: 05/27/2025] [Indexed: 06/11/2025] Open
Abstract
Visceral leishmaniasis (VL) is a zoonotic disease caused by infection of macrophages by Leishmania donovani or L. infantum, and exhibits symptoms such as fever, anemia, and hepatosplenomegaly. VL during pregnancy has been reported to have negative effects such as miscarriage and vertical infection, but the mechanism is not clear. Here, we aimed to establish a pregnant VL mouse model and elucidate its immunopathology. Female BALB/c mice mated 6 months after L. donovani infection showed reduced pregnancy rates. The fetus was removed by caesarean section on the 18th day of pregnancy, and Leishmania parasite DNA was detected from fetal spleens and livers. As a result, the PCR positive rate was 68.9% (71/103 fetus), and vertical transmission was suspected in 66.7% of infected mothers (12/18 dams). Immunohistochemistry in the fetal livers detected cells positive for the Leishmania antigen, kinetoplastid membrane protein 11 (KMP11). In addition, pathological analysis of the VL placenta revealed trophoblast cell atrophy and vasodilation accompanied by CD3+ cell infiltration in the infected group. On the other hand, few KMP11+ cells were observed in the placenta of the infected group. Furthermore, RNA-Seq analysis revealed that IFN signal activation and cellular immune suppression were induced in the placenta of the infected group. These results suggest that VL in pregnancy induces suppression of placental cellular immunity through IFN and collapse of the placental barrier through trophoblast degeneration, leading to vertical transmission. Because few infected macrophages were observed in the placenta, it is possible that free Leishmania parasites in the blood contribute to transmission across the placenta.
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Affiliation(s)
- Haruka Mizobuchi
- Laboratory of Molecular Immunology, Department of Animal Resource Sciences, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Junya Yamagishi
- International Collaboration Unit, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan
- Division of Collaboration and Education, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan
| | - Chizu Sanjoba
- Laboratory of Molecular Immunology, Department of Animal Resource Sciences, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Yasuyuki Goto
- Laboratory of Molecular Immunology, Department of Animal Resource Sciences, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
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Mo PL, Lin M, Gao BW, Zhang SB, Chen JP. Knowledge structure analysis and network visualization of tumor-associated macrophages in hepatocellular carcinoma research: A bibliometric mapping. World J Clin Oncol 2025; 16:102747. [DOI: 10.5306/wjco.v16.i5.102747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2024] [Revised: 02/13/2025] [Accepted: 04/11/2025] [Indexed: 05/19/2025] Open
Abstract
BACKGROUND Tumor-associated macrophages (TAMs) have demonstrated significant potential as a research and treatment approach for hepatocellular carcinoma (HCC). Nevertheless, a comprehensive quantitative analysis of TAMs in HCC remained insufficient. Therefore, the objective of this study was to employ bibliometric methods to investigate the development trends and research frontiers pertaining to this field.
AIM To determine the knowledge structure and current research hotspots by bibliometric analysis of scholarly papers pertaining to TAMs in HCC.
METHODS The present study employed the Web of Science Core Collection to identify all papers related to TAMs in HCC research. Utilizing the Analysis Platform of Bibliometrics, CiteSpace 6.2.R4, and Vosviewer 1.6.19, the study conducted a comprehensive analysis encompassing multiple dimensions such as publication quantity, countries of origin, affiliated institutions, publishing journals, contributing authors, co-references, author keywords, and emerging frontiers within this research domain.
RESULTS A thorough examination was undertaken on 818 papers within this particular field, published between January 1, 1985 to September 1, 2023, which has witnessed a substantial surge in scholarly contributions since 2012, with a notable outbreak in 2019. China was serving as the central hub in this field, with Fudan University leading in terms of publications and citations. Chinese scholars have taken the forefront in driving the research expansion within this field. Hepatology emerged as the most influential journal in this field. The study by Qian and Pollard in 2010 received the highest number of co-citations. It was observed that the citation bursts of references coincided with the outbreak of publications. Notably, “tumor microenvironment”, “immunotherapy”, “prognostic”, “inflammation”, and “polarization”, etc. emerged as frequently occurring keywords in this field. Of particular interest, “immune evasion”, “immune infiltration”, and “cancer genome atlas” were identified as emerging frontiers in recent research.
CONCLUSION The field of TAMs in HCC exhibited considerable potential, as evidenced by the promising prospects of immunotherapeutic interventions targeting TAMs for the amelioration of HCC. The emerging frontiers in this field primarily revolved around modulating the immunosuppressive characteristics of TAMs within a liver-specific immune environment, with a focus on how to counter immune evasion and reduce immune infiltration.
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Affiliation(s)
- Ping-Li Mo
- Shenzhen Key Laboratory of Hospital Chinese Medicine Preparation, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen 518033, Guangdong Province, China
| | - Ming Lin
- Department of Hepatology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510120, Guangdong Province, China
| | - Bo-Wen Gao
- Department of Traditional Chinese Medicine, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen 518107, Guangdong Province, China
| | - Shang-Bin Zhang
- Shenzhen Key Laboratory of Hospital Chinese Medicine Preparation, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen 518033, Guangdong Province, China
| | - Jian-Ping Chen
- Shenzhen Key Laboratory of Hospital Chinese Medicine Preparation, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen 518033, Guangdong Province, China
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de Kleine RH, Carbo EC, Lexmond WS, Zhou XW, de Kroon A, Mei H, Bontemps STH, Hennevelt R, Gard L, Sidorov IA, Boers SA, van den Heuvel MC, Buddingh EP, Kroes ACM, de Meijer VE, Schölvinck EH, von Eije KJ, Jochems SP, de Vries JJC. Metagenomic and transcriptomic investigation of pediatric acute liver failure cases reveals a common pathway predominated by monocytes. mBio 2025; 16:e0391324. [PMID: 40099881 PMCID: PMC11980388 DOI: 10.1128/mbio.03913-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Accepted: 02/13/2025] [Indexed: 03/20/2025] Open
Abstract
In 2022, a cluster of severe childhood hepatitis was detected primarily in Europe and North America, leading to a global alert by the World Health Organization. An association with adeno-associated virus 2 (AAV2) in conjunction with human adenoviruses was found. Five percent of the cases progressed to acute liver failure, necessitating transplantation. The mechanism of disease that accounts for fulminant liver failure in these patients remains incompletely described. An upsurge was observed of in the five total cases of acute liver failure that presented to the Dutch national referral center for pediatric liver transplantation in the spring of 2022. An in-depth molecular analysis of the mechanism of pediatric acute liver failure was performed using targeted transcriptomics and metagenomics to identify any virus present in the cases, immune profile haplotypes, and differentially expressed gene groups. Explanted liver tissue and plasma samples (n = 15) were subjected to viral metagenomic and human transcriptomic profiling, targeting >600 inflammatory genes. Liver transcriptomic signatures of transplanted cases were compared with those of pediatric controls from a liver biobank (n = 6). AAV2, adenoviruses, and herpesviruses were detected in liver explant tissue and plasma samples of the cases. Epstein-Barr virus and varicella zoster virus infection with pathognomonic clinical symptomatology preceded liver failure in two respective cases. AAV2 was detected in one-third of control livers. Excessive activation of monocyte pathways was detected in liver explants from cases compared with controls. Remarkably, this signature was comparable for AAV2, adenoviruses, and/or herpesviruses-positive transplant cases. Our multi-omic findings suggest a common transcriptomic profile, with an upregulation of monocyte pathways in the presented transplanted cases, which had similar severe clinical outcomes. In the cohort presented, AAV2 was not exclusively associated with acute liver failure, suggesting that other processes may have contributed to a uniform cascade of irreversible pathology. IMPORTANCE Since the appearance of the cluster of pediatric hepatitis of unknown origin in 2022, several groups have reported an association of adenoviruses and AAV2 in a high number of cases in contrast to controls. The adenoviruses detected were heterogeneous in both species-adenovirus C and F-and sequences. The mechanisms of disease that accounts for fulminant liver failure, occurring in 5% of pediatric hepatitis cases, remain incompletely described. The current study adds to previous data by including pediatric acute liver failure cases during the upsurge, enabling the analyses of inflammation expression profiles in cases with different viruses in relation to pediatric controls. This led to the discovery of transcriptome upregulation of monocyte pathways in liver explants from the cases. This inflammatory transcriptomic signature was comparable for AAV2, adenoviruses, and/or herpesviruses-positive transplant cases.
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Affiliation(s)
- Ruben H. de Kleine
- Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Ellen C. Carbo
- Leiden University Center for Infectious Diseases (LUCID), Leiden University Medical Center, Leiden, The Netherlands
| | - Willem S. Lexmond
- Department of Pediatrics, Section of Paediatric Gastroenterology and Hepatology, Beatrix Children’s Hospital, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Xuewei W. Zhou
- Department of Medical Microbiology, University of Groningen, University Medical Center Groningen, Groningen, Groningen, The Netherlands
| | - Alicia de Kroon
- Leiden University Center for Infectious Diseases (LUCID), Leiden University Medical Center, Leiden, The Netherlands
| | - Hailiang Mei
- Sequencing Analysis Support Core, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands
| | - Sander T. H. Bontemps
- Department of Pediatric Intensive Care, Beatrix Children’s Hospital, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | | | - Lilli Gard
- Department of Medical Microbiology, University of Groningen, University Medical Center Groningen, Groningen, Groningen, The Netherlands
| | - Igor A. Sidorov
- Leiden University Center for Infectious Diseases (LUCID), Leiden University Medical Center, Leiden, The Netherlands
| | - Stefan A. Boers
- Leiden University Center for Infectious Diseases (LUCID), Leiden University Medical Center, Leiden, The Netherlands
| | - Marius C. van den Heuvel
- Department of Pathology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Emilie P. Buddingh
- Willem-Alexander Children’s Hospital, Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands
| | - Aloys C. M. Kroes
- Leiden University Center for Infectious Diseases (LUCID), Leiden University Medical Center, Leiden, The Netherlands
| | - Vincent E. de Meijer
- Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Elisabeth H. Schölvinck
- Department of Pediatrics, Section Infectious Diseases and Immunology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Karin J. von Eije
- Department of Medical Microbiology, University of Groningen, University Medical Center Groningen, Groningen, Groningen, The Netherlands
| | - Simon P. Jochems
- Leiden University Center for Infectious Diseases (LUCID), Leiden University Medical Center, Leiden, The Netherlands
| | - Jutte J. C. de Vries
- Leiden University Center for Infectious Diseases (LUCID), Leiden University Medical Center, Leiden, The Netherlands
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Shin S, Baek DS, Mellors JW, Dimitrov DS, Li W. Development of Fully Human Antibodies Targeting SIRPα and PLA2G7 for Cancer Therapy. Antibodies (Basel) 2025; 14:21. [PMID: 40136470 PMCID: PMC11939323 DOI: 10.3390/antib14010021] [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: 10/30/2024] [Revised: 01/12/2025] [Accepted: 02/25/2025] [Indexed: 03/27/2025] Open
Abstract
Background: Macrophages play an important role in eliminating diseased and damaged cells through programmed cell death. Signal regulatory protein alpha (SIRPα) is a crucial immune checkpoint primarily expressed on myeloid cells and macrophages. It initiates a 'do not eat me' signal when engaged with CD47, which is typically expressed at elevated levels on multiple solid tumors. The phospholipase A2 Group 7 (PLA2G7), which is mainly secreted by macrophages, interacts with oxidized low-density lipoprotein (oxLDL) and associates with several vascular diseases and cancers. Methods: To identify potent fully human monoclonal antibodies (mAbs) against human SIRPα and PLA2G7, we conducted bio-panning of phage antibody libraries. Results: We isolated one human Fab (1B3) and VH (1A3) for SIRPα, as well as one human Fab (1H8) and one VH (1A9) for PLA2G7; the 1B3 Fab and 1A3 VH are competitively bound to SIRPα, interfering with CD47 binding. The 1B3 IgG and 1A3 VH-Fc augmented macrophage-mediated phagocytic activity when combined with the anti-EGFR antibody, cetuximab. The anti-PLA2G7 antibodies exhibited high specificity for the PLA2G7 antigen and effectively blocked the PLA2G7 enzymatic activity with half-maximal inhibitory concentrations (IC50) in the single-digit nanomolar range. Additionally, 1H8 IgG and its derivative bispecific antibody exhibited the ability to block PLA2G7-mediated tumor cell migration. Conclusions: Our anti-SIRPα mAbs are expected to serve as potent and fully human immune checkpoint inhibitors of SIRPα, enhancing the antitumor responses of SIRPα-positive immune cells. Moreover, our anti-PLA2G7 mAbs represent promising fully human PLA2G7 enzymatic blockade antibodies with the potential to enhance both anti-tumor and anti-aging responses. Anti-SIRPα and PLA2G7 mAbs can modulate macrophage phagocytic activity and inflammatory responses against tumors.
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Affiliation(s)
- Seungmin Shin
- Center for Antibody Therapeutics, Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA; (D.-S.B.); (J.W.M.); (D.S.D.)
| | - Du-San Baek
- Center for Antibody Therapeutics, Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA; (D.-S.B.); (J.W.M.); (D.S.D.)
- GLPG US, 1401 Forbes Avenue, Pittsburgh, PA 15219, USA
| | - John W. Mellors
- Center for Antibody Therapeutics, Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA; (D.-S.B.); (J.W.M.); (D.S.D.)
- GLPG US, 1401 Forbes Avenue, Pittsburgh, PA 15219, USA
| | - Dimiter S. Dimitrov
- Center for Antibody Therapeutics, Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA; (D.-S.B.); (J.W.M.); (D.S.D.)
- GLPG US, 1401 Forbes Avenue, Pittsburgh, PA 15219, USA
| | - Wei Li
- Center for Antibody Therapeutics, Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA; (D.-S.B.); (J.W.M.); (D.S.D.)
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Feng S, Zhou M, Huang Z, Xiao X, Zhong B. A colorectal liver metastasis prediction model based on the combination of lipoprotein-associated phospholipase A2 and serum biomarker levels. Clin Chim Acta 2025; 568:120143. [PMID: 39826573 DOI: 10.1016/j.cca.2025.120143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Revised: 01/14/2025] [Accepted: 01/15/2025] [Indexed: 01/22/2025]
Abstract
OBJECTIVE This study aims to assess the predictive value of serum lipoprotein-associated phospholipase A2 (Lp-PLA2) in colorectal liver metastasis (CRLM) patients. METHODS A total of 507 participants were recruited for this study, comprising 162 healthy controls (HCs), 186 non-CRLM patients, and 159 CRLM patients. Serum Lp-PLA2 levels were measured across these three groups, and a CRLM prediction model was developed using machine learning (ML) algorithms in conjunction with traditional serological markers. The performance of each model was assessed using the area under the receiver operating characteristic (ROC) curve (AUC), sensitivity, specificity, and other relevant metrics. RESULTS The serum Lp-PLA2 levels in CRLM patients were significantly elevated compared to those in HCs group and the non-CRLM group (P < 0.0001). The CRLM prediction model developed using the Random forest algorithm demonstrated superior performance, incorporating six features: Lp-PLA2, ALB, GLB, ALT, LDH, and TC. This model achieved an AUC of 0.918, with a sensitivity of 0.823, specificity of 0.889, positive predictive value (PPV) of 0.861, and negative predictive value (NPV) of 0.857. CONCLUSION The Random forest model, incorporating serum Lp-PLA2 level and conventional laboratory parameters, demonstrates robust predictive capability for CRLM and holds promise for enhancing early detection in CRLM patients.
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Affiliation(s)
- Sisi Feng
- Department of Clinical Laboratory, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| | - Manli Zhou
- Department of Clinical Laboratory, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| | - Zixin Huang
- Department of Clinical Laboratory, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| | - Xiaomin Xiao
- Department of Clinical Laboratory, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
| | - Baiyun Zhong
- Department of Clinical Laboratory, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China.
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Ping Y, Fan Q, Zhang Y. Modulating lipid metabolism improves tumor immunotherapy. J Immunother Cancer 2025; 13:e010824. [PMID: 39904563 PMCID: PMC11795363 DOI: 10.1136/jitc-2024-010824] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2024] [Accepted: 01/21/2025] [Indexed: 02/06/2025] Open
Abstract
Immunotherapy has progressed significantly in cancer treatment; however, several factors influence its outcomes. Abnormal lipid metabolism, which is frequently observed in cancers, promotes tumor proliferation, invasion, and metastasis. Li et al from the Medical Oncology Department of Chongqing University Cancer Hospital constructed a lipid metabolism scoring system and reported that MK1775 inhibited fatty acid oxidation in tumor-associated macrophages and reduced T-cell infiltration, further enhancing the efficacy of immunotherapy. This study demonstrated the critical role of lipid metabolism scoring system and lipid metabolism in immunotherapy. Currently, the metabolism of lipids, such as fatty acids, phospholipids, and cholesterol, has been reported to affect the tumor microenvironment by regulating immune cells, including T cells, natural killer cells, and macrophages. These metabolic changes can impair the efficacy of immunotherapy, resulting in tumor progression. Consequently, lipid metabolism emerges as an important immune regulator for improving immunotherapeutic outcomes and provides a novel and powerful strategy for tumor combination therapy.
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Affiliation(s)
- Yu Ping
- Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Qiuqing Fan
- Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Yi Zhang
- Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou, Henan, China
- School of Life Sciences, Zhengzhou University, Zhengzhou, Henan, China
- Tianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China
- School of Public Health, Zhengzhou University, Zhengzhou, Henan, China
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Li W, He H, Wang H, Wen W. Dynamics of liver cancer cellular taxa revealed through single-cell RNA sequencing: Advances and challenges. Cancer Lett 2024; 611:217394. [PMID: 39689824 DOI: 10.1016/j.canlet.2024.217394] [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: 08/20/2024] [Revised: 10/13/2024] [Accepted: 12/14/2024] [Indexed: 12/19/2024]
Abstract
Liver cancer is a leading cause of death worldwide, representing a substantial public health challenge. The advent of single-cell RNA sequencing has significantly advanced our understanding of cellular dynamics from the onset of liver cancer to therapeutic intervention. This technology has unveiled profound insights into cancer heterogeneity and the tumor microenvironment (TME), enabling the identification of key molecular drivers and phenotypic landscapes of liver cancer at a single-cell resolution. This review highlights recent advancements in mapping functional cell subsets, phenotypic alterations, and the diversity of the TME. These insights are pivotal for advancing targeted therapies and developing prognostic tools. Moreover, this review covers the ongoing challenges and advances from tumor initiation to progression, offering a detailed perspective on advancing personalized treatment.
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Affiliation(s)
- Wenxin Li
- Third Affiliated Hospital of Naval Medical University (Second Military Medical University), National Center for Liver Cancer, Shanghai, 200438, China; Department of Clinical Laboratory Medicine, Third Affiliated Hospital of Naval Medical University (Second Military Medical University), Shanghai, 200438, China
| | - Huisi He
- Third Affiliated Hospital of Naval Medical University (Second Military Medical University), National Center for Liver Cancer, Shanghai, 200438, China; Department of Oncology, Third Affiliated Hospital of Naval Medical University (Second Military Medical University), Shanghai, 200438, China
| | - Hongyang Wang
- Third Affiliated Hospital of Naval Medical University (Second Military Medical University), National Center for Liver Cancer, Shanghai, 200438, China; The Ministry of Education Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Shanghai, 200438, China.
| | - Wen Wen
- Third Affiliated Hospital of Naval Medical University (Second Military Medical University), National Center for Liver Cancer, Shanghai, 200438, China; Department of Clinical Laboratory Medicine, Third Affiliated Hospital of Naval Medical University (Second Military Medical University), Shanghai, 200438, China; The Ministry of Education Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Shanghai, 200438, China.
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Huang H, Peng S, Wei Y, Lan C, Qin W, Liao X, Yang CK, Zhu G, Zhou X, Peng T. Dendritic Cell-Related Gene Signatures in Hepatocellular Carcinoma: An Analysis for Prognosis and Therapy Efficacy Evaluation. J Hepatocell Carcinoma 2024; 11:1743-1761. [PMID: 39309303 PMCID: PMC11416124 DOI: 10.2147/jhc.s481338] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Accepted: 09/10/2024] [Indexed: 09/25/2024] Open
Abstract
Background This study aimed to identify dendritic cells (DCs) related genes in hepatocellular carcinoma (HCC) patients, establish DC-related subtypes and signatures, and correlate them with prognosis and treatment response. Methods DC-related genes were screened using Weighted Gene Co-expression Network Analysis (WGCNA) based on RNA sequencing from the TCGA (374 samples), GSE14520 (242 samples), and GSE76427 datasets (115 samples), following immune infiltration assessment by the TIME method. Two DC-related subtypes in HCC were identified through unsupervised clustering. A DC-related signature (DCRS) predictive of overall survival was constructed using LASSO and Cox regression models, and validated across the three datasets. Additionally, genetic mutation characteristics, immune infiltration levels, and treatment sensitivity were explored in DCRS risk groups. The expression levels of DCRS genes and risk scores were validated in the transcriptome of 13 HCC patients receiving combined targeted therapy and immunotherapy in the Guangxi cohort using Wilcoxon test. Results A signature consisting of 13 genes related to DCs was constructed, and the superior prognostic consistency of the low DCRS risk group was validated across the TCGA (P=0.003), GSE76427 (P=0.005), and GSE14520 (P=0.047) datasets. Furthermore, in the 147-sample transarterial chemoembolization (TACE) treatment dataset GSE104580, the response group exhibited lower risk scores than the non-response group (P=0.01), whereas in the 140-sample Sorafenib treatment dataset GSE109211 (P=0.041) and the 17-sample anti-PD-1 treatment dataset GSE202069 (P=0.027), the risk scores were higher in the response group. We also validated the gene expression levels of DCRS and the higher risk scores in the response group of the Guangxi cohort (P=0.034). Conclusion A DCRS consisting of 13 genes was established in HCC, facilitating the prediction of patient prognosis and responsiveness to TACE, targeted therapy, and immunotherapy.
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Affiliation(s)
- Huasheng Huang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China
- Guangxi Key Laboratory of Enhanced Recovery After Surgery for Gastrointestinal Cancer, Nanning, People’s Republic of China
- Key Laboratory of Early Prevention & Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China
| | - Shayong Peng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China
- Guangxi Key Laboratory of Enhanced Recovery After Surgery for Gastrointestinal Cancer, Nanning, People’s Republic of China
- Key Laboratory of Early Prevention & Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China
| | - Yongguang Wei
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China
- Guangxi Key Laboratory of Enhanced Recovery After Surgery for Gastrointestinal Cancer, Nanning, People’s Republic of China
- Key Laboratory of Early Prevention & Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China
| | - Chenlu Lan
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China
- Guangxi Key Laboratory of Enhanced Recovery After Surgery for Gastrointestinal Cancer, Nanning, People’s Republic of China
- Key Laboratory of Early Prevention & Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China
| | - Wei Qin
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China
- Guangxi Key Laboratory of Enhanced Recovery After Surgery for Gastrointestinal Cancer, Nanning, People’s Republic of China
- Key Laboratory of Early Prevention & Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China
| | - Xiwen Liao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China
- Guangxi Key Laboratory of Enhanced Recovery After Surgery for Gastrointestinal Cancer, Nanning, People’s Republic of China
- Key Laboratory of Early Prevention & Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China
| | - Cheng-Kun Yang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China
- Guangxi Key Laboratory of Enhanced Recovery After Surgery for Gastrointestinal Cancer, Nanning, People’s Republic of China
- Key Laboratory of Early Prevention & Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China
| | - Guangzhi Zhu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China
- Guangxi Key Laboratory of Enhanced Recovery After Surgery for Gastrointestinal Cancer, Nanning, People’s Republic of China
- Key Laboratory of Early Prevention & Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China
| | - Xin Zhou
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China
- Guangxi Key Laboratory of Enhanced Recovery After Surgery for Gastrointestinal Cancer, Nanning, People’s Republic of China
- Key Laboratory of Early Prevention & Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China
| | - Tao Peng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China
- Guangxi Key Laboratory of Enhanced Recovery After Surgery for Gastrointestinal Cancer, Nanning, People’s Republic of China
- Key Laboratory of Early Prevention & Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China
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10
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Sati S, Huang J, Kersh AE, Jones P, Ahart O, Murphy C, Prouty SM, Hedberg ML, Jain V, Gregory SG, Leung DH, Seykora JT, Rosenbach M, Leung TH. Recruitment of CXCR4+ type 1 innate lymphoid cells distinguishes sarcoidosis from other skin granulomatous diseases. J Clin Invest 2024; 134:e178711. [PMID: 39225100 PMCID: PMC11364400 DOI: 10.1172/jci178711] [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: 12/20/2023] [Accepted: 06/25/2024] [Indexed: 09/04/2024] Open
Abstract
Sarcoidosis is a multiorgan granulomatous disease that lacks diagnostic biomarkers and targeted treatments. Using blood and skin from patients with sarcoid and non-sarcoid skin granulomas, we discovered that skin granulomas from different diseases exhibit unique immune cell recruitment and molecular signatures. Sarcoid skin granulomas were specifically enriched for type 1 innate lymphoid cells (ILC1s) and B cells and exhibited molecular programs associated with formation of mature tertiary lymphoid structures (TLSs), including increased CXCL12/CXCR4 signaling. Lung sarcoidosis granulomas also displayed similar immune cell recruitment. Thus, granuloma formation was not a generic molecular response. In addition to tissue-specific effects, patients with sarcoidosis exhibited an 8-fold increase in circulating ILC1s, which correlated with treatment status. Multiple immune cell types induced CXCL12/CXCR4 signaling in sarcoidosis, including Th1 T cells, macrophages, and ILCs. Mechanistically, CXCR4 inhibition reduced sarcoidosis-activated immune cell migration, and targeting CXCR4 or total ILCs attenuated granuloma formation in a noninfectious mouse model. Taken together, our results show that ILC1s are a tissue and circulating biomarker that distinguishes sarcoidosis from other skin granulomatous diseases. Repurposing existing CXCR4 inhibitors may offer a new targeted treatment for this devastating disease.
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Affiliation(s)
- Satish Sati
- Department of Dermatology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
| | - Jianhe Huang
- Department of Dermatology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
| | - Anna E. Kersh
- Department of Dermatology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
| | - Parker Jones
- Department of Dermatology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
| | - Olivia Ahart
- Department of Dermatology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
| | - Christina Murphy
- Department of Dermatology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
| | - Stephen M. Prouty
- Department of Dermatology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
| | - Matthew L. Hedberg
- Department of Dermatology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
| | - Vaibhav Jain
- Duke Molecular Physiology Institute, Durham, North Carolina, USA
| | - Simon G. Gregory
- Duke Molecular Physiology Institute, Durham, North Carolina, USA
| | | | - John T. Seykora
- Department of Dermatology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
| | - Misha Rosenbach
- Department of Dermatology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
| | - Thomas H. Leung
- Department of Dermatology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
- Corporal Michael Crescenz Veterans Affairs Medical Center, Philadelphia, Pennsylvania, USA
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11
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Hu N, Li H, Tao C, Xiao T, Rong W. The Role of Metabolic Reprogramming in the Tumor Immune Microenvironment: Mechanisms and Opportunities for Immunotherapy in Hepatocellular Carcinoma. Int J Mol Sci 2024; 25:5584. [PMID: 38891772 PMCID: PMC11171976 DOI: 10.3390/ijms25115584] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 05/16/2024] [Accepted: 05/18/2024] [Indexed: 06/21/2024] Open
Abstract
As one of the emerging hallmarks of tumorigenesis and tumor progression, metabolic remodeling is common in the tumor microenvironment. Hepatocellular carcinoma (HCC) is the third leading cause of global tumor-related mortality, causing a series of metabolic alterations in response to nutrient availability and consumption to fulfill the demands of biosynthesis and carcinogenesis. Despite the efficacy of immunotherapy in treating HCC, the response rate remains unsatisfactory. Recently, research has focused on metabolic reprogramming and its effects on the immune state of the tumor microenvironment, and immune response rate. In this review, we delineate the metabolic reprogramming observed in HCC and its influence on the tumor immune microenvironment. We discuss strategies aimed at enhancing response rates and overcoming immune resistance through metabolic interventions, focusing on targeting glucose, lipid, or amino acid metabolism, as well as systemic regulation.
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Affiliation(s)
- Nan Hu
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China; (N.H.); (H.L.); (C.T.)
| | - Haiyang Li
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China; (N.H.); (H.L.); (C.T.)
| | - Changcheng Tao
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China; (N.H.); (H.L.); (C.T.)
| | - Ting Xiao
- State Key Laboratory of Molecular Oncology, Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Weiqi Rong
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China; (N.H.); (H.L.); (C.T.)
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12
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Nair R, Lannagan TRM, Jackstadt R, Andrusaite A, Cole J, Boyne C, Nibbs RJB, Sansom OJ, Milling S. Co-inhibition of TGF-β and PD-L1 pathways in a metastatic colorectal cancer mouse model triggers interferon responses, innate cells and T cells, alongside metabolic changes and tumor resistance. Oncoimmunology 2024; 13:2330194. [PMID: 38516270 PMCID: PMC10956632 DOI: 10.1080/2162402x.2024.2330194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2023] [Accepted: 03/11/2024] [Indexed: 03/23/2024] Open
Abstract
Colorectal cancer (CRC) is the third most prevalent cancer worldwide with a high mortality rate (20-30%), especially due to metastasis to adjacent organs. Clinical responses to chemotherapy, radiation, targeted and immunotherapies are limited to a subset of patients making metastatic CRC (mCRC) difficult to treat. To understand the therapeutic modulation of immune response in mCRC, we have used a genetically engineered mouse model (GEMM), "KPN", which resembles the human 'CMS4'-like subtype. We show here that transforming growth factor (TGF-β1), secreted by KPN organoids, increases cancer cell proliferation, and inhibits splenocyte activation in vitro. TGF-β1 also inhibits activation of naive but not pre-activated T cells, suggesting differential effects on specific immune cells. In vivo, the inhibition of TGF-β inflames the KPN tumors, causing infiltration of T cells, monocytes and monocytic intermediates, while reducing neutrophils and epithelial cells. Co-inhibition of TGF-β and PD-L1 signaling further enhances cytotoxic CD8+T cells and upregulates innate immune response and interferon gene signatures. However, simultaneous upregulation of cancer-related metabolic genes correlated with limited control of tumor burden and/or progression despite combination treatment. Our study illustrates the importance of using GEMMs to predict better immunotherapies for mCRC.
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Affiliation(s)
- Reshmi Nair
- School of infection and immunity, University of Glasgow, Glasgow, UK
| | | | | | - Anna Andrusaite
- School of infection and immunity, University of Glasgow, Glasgow, UK
| | - John Cole
- School of infection and immunity, University of Glasgow, Glasgow, UK
| | - Caitlin Boyne
- School of infection and immunity, University of Glasgow, Glasgow, UK
| | | | - Owen J. Sansom
- Cancer Research UK Scotland Institute, Glasgow, UK
- School of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Simon Milling
- School of infection and immunity, University of Glasgow, Glasgow, UK
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