The Profiles of Immunosuppressive Microenvironment in the Lauren Intestinal-type Gastric Adenocarcinoma

Overview

Journal Cancer Immunol Immunother

Date 2025 Feb 1

PMID 39891785

Authors

Qingyuan Wang

Jia Chen

Yaohui Wang

Xiang Li

Xiaochun Ping

Jiajia Shen

Sheng Yang

Lizong Shen

Affiliations

Soon will be listed here.

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 (HAVCR2VCAM1) and regulatory T cells (Tregs) (LAYNTNFRSF4) 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 HAVCR2VCAM1 Texs and LAYNTNFRSF4 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.

References

Han B, Zheng R, Zeng H, Wang S, Sun K, Chen R . Cancer incidence and mortality in China, 2022. J Natl Cancer Cent. 2024; 4(1):47-53. PMC: 11256708. DOI: 10.1016/j.jncc.2024.01.006. View

Smyth E, Nilsson M, Grabsch H, van Grieken N, Lordick F . Gastric cancer. Lancet. 2020; 396(10251):635-648. DOI: 10.1016/S0140-6736(20)31288-5. View

Wagner A, Syn N, Moehler M, Grothe W, Yong W, Tai B . Chemotherapy for advanced gastric cancer. Cochrane Database Syst Rev. 2017; 8:CD004064. PMC: 6483552. DOI: 10.1002/14651858.CD004064.pub4. View

Tie Y, Tang F, Wei Y, Wei X . Immunosuppressive cells in cancer: mechanisms and potential therapeutic targets. J Hematol Oncol. 2022; 15(1):61. PMC: 9118588. DOI: 10.1186/s13045-022-01282-8. View

Powles T, Plimack E, Soulieres D, Waddell T, Stus V, Gafanov R . Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial. Lancet Oncol. 2020; 21(12):1563-1573. DOI: 10.1016/S1470-2045(20)30436-8. View

Booth M, Smyth E . Immunotherapy in Gastro-Oesophageal Cancer: Current Practice and the Future of Personalised Therapy. BioDrugs. 2022; 36(4):473-485. DOI: 10.1007/s40259-022-00527-9. View

Fuchs C, Ozguroglu M, Bang Y, Di Bartolomeo M, Mandala M, Ryu M . Pembrolizumab versus paclitaxel for previously treated PD-L1-positive advanced gastric or gastroesophageal junction cancer: 2-year update of the randomized phase 3 KEYNOTE-061 trial. Gastric Cancer. 2021; 25(1):197-206. PMC: 8732941. DOI: 10.1007/s10120-021-01227-z. View

Shitara K, Van Cutsem E, Bang Y, Fuchs C, Wyrwicz L, Lee K . Efficacy and Safety of Pembrolizumab or Pembrolizumab Plus Chemotherapy vs Chemotherapy Alone for Patients With First-line, Advanced Gastric Cancer: The KEYNOTE-062 Phase 3 Randomized Clinical Trial. JAMA Oncol. 2020; 6(10):1571-1580. PMC: 7489405. DOI: 10.1001/jamaoncol.2020.3370. View

Chung H, Kang Y, Chen Z, Bai Y, Wan Ishak W, Shim B . Pembrolizumab versus paclitaxel for previously treated advanced gastric or gastroesophageal junction cancer (KEYNOTE-063): A randomized, open-label, phase 3 trial in Asian patients. Cancer. 2021; 128(5):995-1003. PMC: 9299889. DOI: 10.1002/cncr.34019. View

10.

Moehler M, Dvorkin M, Boku N, Ozguroglu M, Ryu M, Muntean A . Phase III Trial of Avelumab Maintenance After First-Line Induction Chemotherapy Versus Continuation of Chemotherapy in Patients With Gastric Cancers: Results From JAVELIN Gastric 100. J Clin Oncol. 2020; 39(9):966-977. PMC: 8078426. DOI: 10.1200/JCO.20.00892. View

11.

Bang Y, Ruiz E, Van Cutsem E, Lee K, Wyrwicz L, Schenker M . Phase III, randomised trial of avelumab versus physician's choice of chemotherapy as third-line treatment of patients with advanced gastric or gastro-oesophageal junction cancer: primary analysis of JAVELIN Gastric 300. Ann Oncol. 2018; 29(10):2052-2060. PMC: 6225815. DOI: 10.1093/annonc/mdy264. View

12.

Janjigian Y, Shitara K, Moehler M, Garrido M, Salman P, Shen L . First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet. 2021; 398(10294):27-40. PMC: 8436782. DOI: 10.1016/S0140-6736(21)00797-2. View

13.

Fu T, Dai L, Wu S, Xiao Y, Ma D, Jiang Y . Spatial architecture of the immune microenvironment orchestrates tumor immunity and therapeutic response. J Hematol Oncol. 2021; 14(1):98. PMC: 8234625. DOI: 10.1186/s13045-021-01103-4. View

14.

Chen Y, Jia K, Sun Y, Zhang C, Li Y, Zhang L . Predicting response to immunotherapy in gastric cancer via multi-dimensional analyses of the tumour immune microenvironment. Nat Commun. 2022; 13(1):4851. PMC: 9388563. DOI: 10.1038/s41467-022-32570-z. View

15.

Christodoulou M, Zaravinos A . Single-Cell Analysis in Immuno-Oncology. Int J Mol Sci. 2023; 24(9). PMC: 10178969. DOI: 10.3390/ijms24098422. View

16.

Kang B, Camps J, Fan B, Jiang H, Ibrahim M, Hu X . Parallel single-cell and bulk transcriptome analyses reveal key features of the gastric tumor microenvironment. Genome Biol. 2022; 23(1):265. PMC: 9773611. DOI: 10.1186/s13059-022-02828-2. View

17.

Wang R, Song S, Qin J, Yoshimura K, Peng F, Chu Y . Evolution of immune and stromal cell states and ecotypes during gastric adenocarcinoma progression. Cancer Cell. 2023; 41(8):1407-1426.e9. PMC: 10528152. DOI: 10.1016/j.ccell.2023.06.005. View

18.

Li Y, Hu X, Lin R, Zhou G, Zhao L, Zhao D . Single-cell landscape reveals active cell subtypes and their interaction in the tumor microenvironment of gastric cancer. Theranostics. 2022; 12(8):3818-3833. PMC: 9131288. DOI: 10.7150/thno.71833. View

19.

Sun K, Xu R, Ma F, Yang N, Li Y, Sun X . scRNA-seq of gastric tumor shows complex intercellular interaction with an alternative T cell exhaustion trajectory. Nat Commun. 2022; 13(1):4943. PMC: 9399107. DOI: 10.1038/s41467-022-32627-z. View

20.

Zhao W, Jia Y, Sun G, Yang H, Liu L, Qu X . Single-cell analysis of gastric signet ring cell carcinoma reveals cytological and immune microenvironment features. Nat Commun. 2023; 14(1):2985. PMC: 10209160. DOI: 10.1038/s41467-023-38426-4. View