CD226 identifies functional CD8+T cells in the tumor microenvironment and predicts a better outcome for human gastric cancer

Hao Huang; Ziyi Huang; Junwei Ge; Jiayi Yang; Junjun Chen; Bin Xu; Shaoxian Wu; Xiao Zheng; Lujun Chen; Xueguang Zhang; Jingting Jiang

doi:10.3389/fimmu.2023.1150803

CD226 identifies functional CD8⁺T cells in the tumor microenvironment and predicts a better outcome for human gastric cancer

Front Immunol. 2023 Mar 28:14:1150803. doi: 10.3389/fimmu.2023.1150803. eCollection 2023.

Authors

Hao Huang^{1

2

3}, Ziyi Huang^{4

5

6}, Junwei Ge^{1

2

3}, Jiayi Yang^{1

2

3}, Junjun Chen^{1

2

3}, Bin Xu^{1

2

3}, Shaoxian Wu^{1

2

3}, Xiao Zheng^{1

2

3}, Lujun Chen^{1

2

3}, Xueguang Zhang^{4

5

6}, Jingting Jiang^{1

2

3}

Affiliations

¹ Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China.
² Jiangsu Engineering Research Center for Tumor Immunotherapy, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China.
³ Institute of Cell Therapy, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China.
⁴ Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
⁵ Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, Jiangsu, China.
⁶ Jiangsu Key Laboratory of Gastrointestinal Tumor Immunology, Soochow University, Suzhou, Jiangsu, China.

Abstract

It is well-known that CD226 serves as a critical activating receptor on various immune cells, such as lymphocytes and monocytes, and it is suggested to promote anti-tumor immunity in the tumor microenvironment (TME). Herein, we showed a crucial regulatory role of CD226 in CD8⁺T cell-mediated anti-tumor response in TME of human gastric cancer (GC). Specifically, the increased CD226 expression in cancer tissues was significantly associated with better clinical outcomes in GC patients. Moreover, the increased infiltrating CD226⁺CD8⁺T cells and the increased ratio of infiltrating CD226⁺CD8⁺T cells in CD8⁺T subpopulation within cancer tissues could also be valuable prognostic predictors for GC patients. Mechanically, the assay for transposase-accessible chromatin using sequencing (ATAC-seq) analysis revealed that the chromatin accessibility of CD226 in CD4⁺ and CD8⁺TILs was significantly higher than that in CD8⁺T cells in normal tissues. Further analysis showed that CD8⁺TILs highly expressed immune checkpoint molecules, such as TIGIT, LAG3, and HAVCR2, which means CD8⁺TILs are more exhausted. In addition, our multi-color immunohistochemical staining (mIHC) revealed that GC patients with higher frequency of IFN-γ⁺CD226⁺CD8⁺TILs showed poorer prognosis. Combined with the single-cell transcriptome sequencing (scRNA-seq) data analysis, we found that the expressions of IFN-γ and TIGIT in CD8⁺TILs were significantly and positively correlated. The expression of TIGIT in IFN-γ⁺CD226⁺CD8⁺TILs was higher, while that in IFN-γ^-CD226⁺CD8⁺TILs was significantly lower. The correlation analysis showed that the expression of CD226 was positively correlated with the score of effector T cells but negatively correlated with that of immunosuppressive factors, such as Tregs and tumor-associated macrophages (TAMs). Collectively, we showed that the frequency of CD226⁺CD8⁺TILs was an excellent prognostic predictor for GC patients. Our findings provided insights into the interaction pattern between co-stimulatory receptor CD226 and tumor cells as well as the infiltrating immune cells in the TME in GC.

Keywords: CD226; CD8+ T cells; gastric cancer; multi-color immunohistochemical staining; prognosis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

CD8-Positive T-Lymphocytes
Humans
Lymphocytes, Tumor-Infiltrating
Receptors, Immunologic / metabolism
Stomach Neoplasms* / genetics
Stomach Neoplasms* / metabolism
Tumor Microenvironment

Substances

Receptors, Immunologic
CD226 antigen

Grants and funding

The present study was supported by the National Natural Science Foundation of China (82172689 and 31729001), the Key R&D Project of Jiangsu Province (BE2022721), the Natural Science Foundation of Jiangsu Province (BK20211065), China Postdoctoral Science Foundation (2021M700543 and 2021M700547), High-Level Talents Project of Jiangsu Commission of Health (LGY2020034), High-Level Talents Project of Changzhou Health Bureau (KY20221390), the Applied Basic Research Foundation of Changzhou (CJ20190094, CJ20210089, CJ20210021 and CE20215030), Changzhou International Cooperation Project (CZ20210035) and Suzhou Science and Technology Program in Medical Health (SKJY2021071).