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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Springer
2025-02-01
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| 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. |
| format | Article |
| id | doaj-art-2b63378eed7b44b58051755706a76b4c |
| institution | Kabale University |
| issn | 1432-0851 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Springer |
| record_format | Article |
| series | Cancer Immunology, Immunotherapy |
| 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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