The profiles of immunosuppressive microenvironment in the Lauren intestinal-type gastric adenocarcinoma

Abstract Background Gastric adenocarcinoma (GAC), particularly the Lauren intestinal-type GAC (IGAC), leads to significant mortality in China due to the limited effectiveness of current treatments. This study aims to investigate the mechanisms of immune suppression in IGAC to identify potential targ...

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Main Authors: Qingyuan Wang, Jia Chen, Yaohui Wang, Xiang Li, Xiaochun Ping, Jiajia Shen, Sheng Yang, Lizong Shen
Format: Article
Language:English
Published: Springer 2025-02-01
Series:Cancer Immunology, Immunotherapy
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Online Access:https://doi.org/10.1007/s00262-024-03938-5
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author Qingyuan Wang
Jia Chen
Yaohui Wang
Xiang Li
Xiaochun Ping
Jiajia Shen
Sheng Yang
Lizong Shen
author_facet Qingyuan Wang
Jia Chen
Yaohui Wang
Xiang Li
Xiaochun Ping
Jiajia Shen
Sheng Yang
Lizong Shen
author_sort Qingyuan Wang
collection DOAJ
description Abstract Background Gastric adenocarcinoma (GAC), particularly the Lauren intestinal-type GAC (IGAC), leads to significant mortality in China due to the limited effectiveness of current treatments. This study aims to investigate the mechanisms of immune suppression in IGAC to identify potential targets for enhancing immunotherapy outcomes. Methods Performing an extensive collection and re-analysis of single-cell RNA sequencing (scRNA-seq) of tumor tissues and the corresponding noncancerous mucosae from 15 Chinese patients diagnosed with IGAC, we identified cell subpopulations involved in immune suppression within the tumor microenvironment (TME). We further validated our findings using spatially resolved transcriptomics (SRT), immunofluorescence (IF), and flow cytometry (FCM) on tissues from IGAC patients. Results We demonstrated that the TME of IGAC harbors CD8+ exhausted T cells (Texs) and various subtypes that mediate immunity. We identified specific subpopulations of Texs (HAVCR2 + VCAM1 +) and regulatory T cells (Tregs) (LAYN + TNFRSF4 +) contributing to immune suppression. Furthermore, TNFRSF12A + cancer-associated fibroblasts (CAFs), CTSB + macrophages, and SOD2 + monocytes were found to be involved in maintaining the immunosuppressive milieu. SRT and IF assays confirmed the presence and colocalization of these cell types within the tumor tissues, highlighting their functional interactions. FCM assays indicated that the prevalence of HAVCR2 + VCAM1 + Texs and LAYN + TNFRSF4 + Tregs in tumor tissues was positively associated with IGAC progression. Conclusions Detailed profiles of immunosuppressive cell subpopulations in IGAC provide valuable insights into the complexity and heterogeneity of immunosuppression. These findings underscore the necessity for targeted strategies that disrupt specific immunosuppressive pathways, potentially enhancing the efficacy of immunotherapeutic interventions in IGAC.
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spelling doaj-art-2b63378eed7b44b58051755706a76b4c2025-02-02T12:26:27ZengSpringerCancer Immunology, Immunotherapy1432-08512025-02-0174311910.1007/s00262-024-03938-5The profiles of immunosuppressive microenvironment in the Lauren intestinal-type gastric adenocarcinomaQingyuan Wang0Jia Chen1Yaohui Wang2Xiang Li3Xiaochun Ping4Jiajia Shen5Sheng Yang6Lizong Shen7Departemtn of General Surgery, the First Affiliated Hospital, Nanjing Medical UniversityDepartemtn of General Surgery, the First Affiliated Hospital, Nanjing Medical UniversityDepartment of Pathology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese MedicineDepartment of Surgical Oncology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese MedicineDepartemtn of General Surgery, the First Affiliated Hospital, Nanjing Medical UniversityDepartemtn of General Surgery, the First Affiliated Hospital, Nanjing Medical UniversityDepartment of Biostatistics, Center for Global Health, School of Public Health, Nanjing Medical UniversityDepartemtn of General Surgery, the First Affiliated Hospital, Nanjing Medical UniversityAbstract Background Gastric adenocarcinoma (GAC), particularly the Lauren intestinal-type GAC (IGAC), leads to significant mortality in China due to the limited effectiveness of current treatments. This study aims to investigate the mechanisms of immune suppression in IGAC to identify potential targets for enhancing immunotherapy outcomes. Methods Performing an extensive collection and re-analysis of single-cell RNA sequencing (scRNA-seq) of tumor tissues and the corresponding noncancerous mucosae from 15 Chinese patients diagnosed with IGAC, we identified cell subpopulations involved in immune suppression within the tumor microenvironment (TME). We further validated our findings using spatially resolved transcriptomics (SRT), immunofluorescence (IF), and flow cytometry (FCM) on tissues from IGAC patients. Results We demonstrated that the TME of IGAC harbors CD8+ exhausted T cells (Texs) and various subtypes that mediate immunity. We identified specific subpopulations of Texs (HAVCR2 + VCAM1 +) and regulatory T cells (Tregs) (LAYN + TNFRSF4 +) contributing to immune suppression. Furthermore, TNFRSF12A + cancer-associated fibroblasts (CAFs), CTSB + macrophages, and SOD2 + monocytes were found to be involved in maintaining the immunosuppressive milieu. SRT and IF assays confirmed the presence and colocalization of these cell types within the tumor tissues, highlighting their functional interactions. FCM assays indicated that the prevalence of HAVCR2 + VCAM1 + Texs and LAYN + TNFRSF4 + Tregs in tumor tissues was positively associated with IGAC progression. Conclusions Detailed profiles of immunosuppressive cell subpopulations in IGAC provide valuable insights into the complexity and heterogeneity of immunosuppression. These findings underscore the necessity for targeted strategies that disrupt specific immunosuppressive pathways, potentially enhancing the efficacy of immunotherapeutic interventions in IGAC.https://doi.org/10.1007/s00262-024-03938-5Intestinal-type gastric adenocarcinomaImmune suppressionT cell exhaustionRegulatory T cellsCancer-associated fibroblasts
spellingShingle Qingyuan Wang
Jia Chen
Yaohui Wang
Xiang Li
Xiaochun Ping
Jiajia Shen
Sheng Yang
Lizong Shen
The profiles of immunosuppressive microenvironment in the Lauren intestinal-type gastric adenocarcinoma
Cancer Immunology, Immunotherapy
Intestinal-type gastric adenocarcinoma
Immune suppression
T cell exhaustion
Regulatory T cells
Cancer-associated fibroblasts
title The profiles of immunosuppressive microenvironment in the Lauren intestinal-type gastric adenocarcinoma
title_full The profiles of immunosuppressive microenvironment in the Lauren intestinal-type gastric adenocarcinoma
title_fullStr The profiles of immunosuppressive microenvironment in the Lauren intestinal-type gastric adenocarcinoma
title_full_unstemmed The profiles of immunosuppressive microenvironment in the Lauren intestinal-type gastric adenocarcinoma
title_short The profiles of immunosuppressive microenvironment in the Lauren intestinal-type gastric adenocarcinoma
title_sort profiles of immunosuppressive microenvironment in the lauren intestinal type gastric adenocarcinoma
topic Intestinal-type gastric adenocarcinoma
Immune suppression
T cell exhaustion
Regulatory T cells
Cancer-associated fibroblasts
url https://doi.org/10.1007/s00262-024-03938-5
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