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-α, IFN-γ and cytolytic molecules than their CD39^-CD4⁺ counterparts. Moreover, ex vivo 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.

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.

CD39; CD4+ T cells; exhaustion; gastric cancer; immunotherapy.