Platelet PD-L1 suppresses anti-cancer immune cell activity in PD-L1 negative tumors
Alexander B. Zaslavsky, Mackenzie Adams, Xuhong Cao, Tomasz Maj, Jae Eun Choi, Judith Stangl‐Kremser, Shivani Patel, Audrey M. Putelo, S. K. Lee, Srinivas Nallandhighal, Amy Kasputis, Ajjai Alva, Madelyn Lew, Angel Qin, Rohit Mehra, Todd M. Morgan, Simpa S. Salami, Zachery R. Reichert, Aaron M. Udager, Weiping Zou, Ganesh S. Palapattu
Abstract
Strategies that interfere with the binding of the receptor programmed cell death protein-1 (PD-1) to programmed death ligand-1 (PD-L1) have shown marked efficacy against many advanced cancers, including those that are negative for PD-L1. Precisely why patients with PD-L1 negative tumors respond to PD-1/PD-L1 checkpoint inhibition remains unclear. Here, we show that platelet-derived PD-L1 regulates the growth of PD-L1 negative tumors and that interference with platelet binding to PD-L1 negative cancer cells promotes T cell-induced cancer cytotoxicity. These results suggest that the successful outcomes of PD-L1 based therapies in patients with PD-L1 negative tumors may be explained, in part, by the presence of intra-tumoral platelets. Altogether, our findings demonstrate the impact of non-cancer/non-immune cell sources of PD-L1 in the tumor microenvironment in the promotion of cancer cell immune evasion. Our study also provides a compelling rationale for future testing of PD-L1 checkpoint inhibitor therapies in combination with antiplatelet agents, in patients with PD-L1 negative tumors.