Hypoxia drives CD39-dependent suppressor function in exhausted T cells to limit antitumor immunity

CD8(+) T cells are critical for elimination of cancer cells. Factors within the tumor microenvironment (TME) can drive these cells to a hypofunctional state known as exhaustion. The most terminally exhausted T (tT(ex)) cells are resistant to checkpoint blockade immunotherapy and might instead limit immunotherapeutic efficacy. Here we show that intratumoral CD8(+) tT(ex) cells possess transcriptional features of CD4(+)Foxp3(+) regulatory T cells and are similarly capable of directly suppressing T cell proliferation ex vivo. tT(ex) cell suppression requires CD39, which generates immunosuppressive adenosine. Restricted deletion of CD39 in endogenous CD8(+) T cells resulted in slowed tumor progression, improved immunotherapy responsiveness and enhanced infiltration of transferred tumor-specific T cells. CD39 is induced on tT(ex) cells by tumor hypoxia, thus mitigation of hypoxia limits tT(ex) suppression. Together, these data suggest tT(ex) cells are an important regulatory population in cancer and strategies to limit their generation, reprogram their immunosuppressive state or remove them from the TME might potentiate immunotherapy.