Targeting adenosine metabolism boosts anti-tumor CD8+ T cell activity and overcomes resistance to immune checkpoint inhibitors in non-small cell lung cancer 3121

Abstract Description Combination treatment with immunotherapy plus concurrent chemotherapy (cisplatin or carboplatin) is now part of the standard of care for many patients with non-small cell lung cancer (NSCLC). Although chemotherapy is known to enhance the efficacy of immunotherapies, whether chemotherapy can also have paradoxical negative effects that diminish immunotherapy efficacy is currently unknown. Our data indicate that cisplatin, a chemotherapy commonly used to treat NSCLC, induces prostaglandin E2 (PGE2) production in tumor cells; PGE2 leads to upregulation of CD73 enzyme on the surface of monocytic myeloid-derived suppressor cells (M-MDSCs). Our data show that CD73+ M-MDSCs catalyzes the production of extracellular adenosine that then inhibits the activation of effector T cells within the tumor microenvironment (TME) and thus limits the efficacy of chemo-immunotherapy. The production of PGE2 from lung tumor cells is regulated by a signaling pathway involving fatty acids, NF-κB, CREB, and COX-2. To deplete the intra-tumoral adenosine, we have explored the use of an FDA approved drug, [PEGylated]-Adenosine Deaminase (PEG-ADA). Our data show that depletion of adenosine with PEG-ADA induces anti-tumor immunity and sensitize NSCLC to immunotherapy. These findings reveal a novel immunosuppressive mechanism driven by cisplatin-induced PGE2 production and suggest that targeting adenosine metabolism is a novel strategy to improve the effectiveness of chemo-immunotherapy in NSCLC. Funding Sources NIH/NCI R01 (1R01CA272772-01A1) to KY Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)