CD38-mediated immunosuppression as a mechanism of tumor cell escape from PD-1/PD-L1 blockade

Although treatment with immune checkpoint inhibitors provides promising benefit for cancer patients, optimal use is encumbered by high resistance rates and requires a thorough understanding of resistance mechanisms. We observed that tumors treated with PD-1/PD-L1 blocking antibodies develop resistance through the up-regulation of CD38, which is induced by all-trans retinoic acid (ATRA) and IFN-β in the tumor microenvironment. In vitro and in vivo studies demonstrate that CD38 inhibits CD8+ T cell function via adenosine receptor signaling, and that CD38 or adenosine receptor blockade are effective strategies to overcome the resistance. Large datasets of human tumors reveal expression of CD38 in a subset of tumors with high levels of basal or treatment-induced T cell infiltration, where immune checkpoint therapies are thought to be most effective. These findings provide a novel mechanism of acquired resistance to immune checkpoint therapy and an opportunity to expand their efficacy in cancer treatment.