The paradoxical significance of CD39+CD8+ T cells in clear cell renal cell carcinoma

CD39+CD8+ T cells are known as tumour antigen-specific cells among CD8+ tumour-infiltrating lymphocytes (TILs). However, CD39+CD8+ T cells also reportedly exhibit immunosuppressive activity in hypoxic tumour models. Here we investigated CD39+CD8+ TILs with regards to their molecular phenotypes, developmental mechanisms, functions, and prognostic significance in clear cell renal cell carcinoma (ccRCC), a VHL mutation-associated hypoxic tumour. Single-cell RNA and TCR analyses confirmed that CD39+CD8+ cells are a terminally exhausted subset of tumour-specific CD8+ TILs. CD39+CD8+ T-cell development was highly correlated with cAMP signals, and was directly induced by cAMP and TCR signallings. Analysis of an RCC cohort revealed a markedly elevated proportion of CD39+ cells among CD8+ TILs in ccRCC, compared to non-ccRCC. Moreover, the proportion of CD39+CD8+ TILs was associated with high tumour mutational burden and hypoxic features. Ex vivo functional assays revealed that CD39+CD8+ TILs exerted immunosuppressive activity on neighbouring CD8+ T cells via ectonucleotidase activity- and adenosine-dependent mechanisms. CD39+CD8+ TIL enrichment predicted poor prognosis of ccRCC patients, yet also predicted favourable treatment responses to anti-PD-1 therapy. This paradoxical prognostic significance in ccRCC is explained by the dual properties of CD39+CD8+ TILs: tumour antigen specificity and immunosuppressive activity.