CD38 as a novel immune checkpoint and a mechanism of resistance to the blockade of the PD-1/PD-L1 axis.

Abstract

79 Background: Although immune checkpoint inhibitors including PD-L1 blockade provide significant clinical benefit for patients with lung cancer, barriers to immunotherapy clinical successes have been due to a high rate of resistance. The therapeutic improvement requires a thorough understanding of the biological process of resistance. Until recently, there have been only a few studies reporting the mechanisms of resistance to PD-L1 blockade. The mechanistic basis remains poorly defined. Methods: In multiple immunocompetent syngeneic and K-rasLA1/+p53R172H?g/+ spontaneous animal models of lung cancer, we have explored the resistance mechanisms using pharmacological and genetic approaches (monoclonal antibody treatment and CRISPR/Cas9-mediated editing). The molecular and immune profiles of the tumor microenvironment were evaluated. More importantly, to determine the applicability to patients with lung cancer, we analyzed 259 patients’ specimens with IHC staining and mined many immune markers in TCGA adeno and squamous datasets. Results: We identified the up-regulation of CD38 on tumor cells as well as enrichment of CD38highTregs and CD38highMDSCs in tumor as the markers of treatment resistance. We observed the same resistance mechanism caused by CD38 in PD-L1 KO mice bearing PD-L1 KO Lewis lung tumors edited with the CRISPR/Cas9 system. Furthermore, by manipulating CD38 on a panel of lung cancer cell lines, in vitro and in vivo data demonstrates that CD38 inhibits CD8+ T cell proliferation, antitumor cytokine secretion, and tumor cell killing capability. To test whether CD38 blockade might be therapeutically efficacious to anti-PD-L1 resistance, we applied the combination therapy of anti-CD38 and anti-PD-L1 and demonstrated dramatic therapeutic benefit on primary tumor growth and metastasis. Additionally, in 259 lung patients, 18.5% of cases exhibited positive staining for CD38 on tumor cells, showing a great potential benefit for treating lung patients. Conclusions: CD38 is defined as a novel immune checkpoint and acts as a mechanism of resistance in the context of PD-L1 therapy. Targeting this novel immune checkpoint may broaden the benefit of PD-L1/PD-1 axis blockade for lung cancer treatment.