Anti–PD-1/PD-L1–mediated acquired resistance is dependent on CD38-generated adenosine in the tumor microenvironment. Anti–PD-1/PD-L1–mediated acquired resistance is dependent on CD38-generated adenosine in the tumor microenvironment. A, Blocking PD-1/PD-L1 interactions increases T-cell infiltration in the tumor microenvironment and induces CD8+ T cell–dependent tumor cell control. B, Anti–PD-1/PD-L1–resistant tumors produce soluble mediators such as IFNβ and ATRA (1) that lead to increased expression of CD38 on tumor cells via RARα (2 and 3) that may catalyze NAD+ to immunosuppressive adenosine via the CD38/CD203a/CD73 pathway (4). Adenosine activates A2AR and A2BR adenosine receptors on CD8+ T cells to suppress their antitumor function (5). C, Anti-CD38 mAb in combination with PD-1/PD-L1 blockade improves antitumor immune responses. Deepak Mittal et al. Cancer Discov 2018;8:1066-1068 ©2018 by American Association for Cancer Research