CD39 identifies an exhausted tumor-reactive CD8 T cell population associated with tumor progression in human gastric cancer.

The ectonucleotidase CD39 has been regarded as a promising immune checkpoint in solid tumors. However, the expression of CD39 by tumor-infiltrating CD8 T cells as well as their potential roles and clinical implications in human gastric cancer (GC) remain largely unknown. Here, we found that GC-infiltrating CD8 T cells contained a fraction of CD39 cells that constituted about 6.6% of total CD8 T cells in tumors. These CD39 cells enriched for GC-infiltrating CD8 T cells with features of exhaustion in transcriptional, phenotypic, metabolic and functional profiles. Additionally, GC-infiltrating CD39CD8 T cells were also identified for tumor-reactive T cells, as these cells expanded in vitro were able to recognize autologous tumor organoids and induced more tumor cell apoptosis than those of expanded their CD39 and CD39CD8 counterparts. Furthermore, CD39 enzymatic activity controlled GC-infiltrating CD39CD8 T cell effector function, and blockade of CD39 efficiently enhanced their production of cytokines IFN-γ and TNF-α. Finally, high percentages of GC-infiltrating CD39CD8 T cells correlated with tumor progression and independently predicted patients' poor overall survival. These findings provide novel insights into the association of CD39 expression level on CD8 T cells with their features and potential clinical implications in GC, and empowering those exhausted tumor-reactive CD39CD8 T cells through CD39 inhibition to circumvent the suppressor program may be an attractive therapeutic strategy against GC.