Tumor-specific but immunosuppressive CD39+CD8+ T cells exhibit double-faceted roles in clear cell renal cell carcinoma.

CD39⁺CD8⁺ T cells are known as tumor-antigen-specific cells among CD8⁺ tumor-infiltrating lymphocytes (TILs). However, CD39⁺CD8⁺ T cells also reportedly exhibit immunosuppressive activity in hypoxic tumor models. Here, we investigate CD39⁺CD8⁺ TILs in clear cell renal cell carcinoma (ccRCC), a Von Hippel-Lindau (VHL) mutation-associated hypoxic tumor. Single-cell analyses confirm that CD39⁺CD8⁺ cells are a terminally exhausted subset of tumor-specific CD8⁺ TILs. CD39⁺CD8⁺ T cell development is directly induced by cAMP and T cell receptor (TCR) signaling. Analysis of a renal cell carcinoma (RCC) cohort reveals that the proportion of CD39⁺CD8⁺ TILs is associated with a high tumor mutational burden and hypoxic features. Ex vivo functional assays reveal that CD39⁺CD8⁺ TILs exert immunosuppressive activity via ectonucleotidase activity- and adenosine-dependent mechanisms. CD39⁺CD8⁺ TIL enrichment predicts poor prognosis in patients with ccRCC yet also predicts favorable treatment responses to anti-programmed cell death protein 1 (PD-1) therapy. This paradoxical prognostic significance in ccRCC is explained by the dual properties of CD39⁺CD8⁺ TILs: tumor antigen specificity and immunosuppressive activity.