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.