CD39 expression defines exhausted CD4 + T cells associated with poor survival and immune evasion in human gastric cancer

• Published in: Clinical & translational immunology Vol. 13; no. 3; p. e1499
• Main Authors: Duan, Zhen-Quan, Li, Yu-Xian, Qiu, Yuan, Shen, Yang, Wang, Ying, Zhang, Yuan-Yuan, Zhu, Bao-Hang, Yu, Xiao-Hong, Tan, Xue-Ling, Chen, Weisan, Zhuang, Yuan, Cheng, Ping, Zhang, Wei-Jun, Zou, Quan-Ming, Ma, Dai-Yuan, Peng, Liu-Sheng
• Format: Journal Article
• Language: English
• Published: Australia John Wiley & Sons, Inc 01.01.2024; John Wiley and Sons Inc; Wiley
• Subjects: CD39; CD4 antigen; CD4+ T cells; CD45RA antigen; Cells; Cytokines; Drug resistance; Effector cells; Enzymatic activity; exhaustion; Flow cytometry; Gastric cancer; Gene expression; Genotype & phenotype; Guanylate cyclase; Immune response; Immunotherapy; Lymphocytes; Lymphocytes T; Memory cells; Original; Patients; PD-1 protein; Phenotypes; Survival analysis; Transcription factors; Tumor necrosis factor-α; γ-Interferon; CD39; exhaustion; gastric cancer; immunotherapy; CD4+ T cells
• ISSN: 2050-0068; 2050-0068
• DOI: 10.1002/cti2.1499

CD4 T cell helper and regulatory function in human cancers has been well characterised. However, the definition of tumor-infiltrating CD4 T cell exhaustion and how it contributes to the immune response and disease progression in human gastric cancer (GC) remain largely unknown. A total of 128 GC patients were enrolled in the study. The expression of CD39 and PD-1 on CD4 T cells in the different samples was analysed by flow cytometry. GC-infiltrating CD4 T cell subpopulations based on CD39 expression were phenotypically and functionally assessed. The role of CD39 in the immune response of GC-infiltrating T cells was investigated by inhibiting CD39 enzymatic activity. In comparison with CD4 T cells from the non-tumor tissues, significantly more GC-infiltrating CD4 T cells expressed CD39. Most GC-infiltrating CD39 CD4 T cells exhibited CD45RA CCR7 effector-memory phenotype expressing more exhaustion-associated inhibitory molecules and transcription factors and produced less TNF-α, IFN-γ and cytolytic molecules than their CD39 CD4 counterparts. Moreover, inhibition of CD39 enzymatic activity enhanced their functional potential reflected by TNF-α and IFN-γ production. Finally, increased percentages of GC-infiltrating CD39 CD4 T cells were positively associated with disease progression and patients' poorer overall survival. Our study demonstrates that CD39 expression defines GC-infiltrating CD4 T cell exhaustion and their immunosuppressive function. Targeting CD39 may be a promising therapeutic strategy for treating GC patients.