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

Objectives. 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. Methods. 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. Results. 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-alpha, IFN-gamma and cytolytic molecules than their CD39-CD4(+) counterparts. Moreover, ex vivo inhibition of CD39 enzymatic activity enhanced their functional potential reflected by TNF-alpha and IFN-gamma production. Finally, increased percentages of GC-infiltrating CD39(+)CD4(+) T cells were positively associated with disease progression and patients' poorer overall survival. Conclusion. 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.