Platelets upregulate tumor programmed death-ligand 1 in an epidermal growth factor receptor-dependent manner in vitro

Programmed death-ligand 1 (PD-L1) is an immune checkpoint protein that suppresses cytotoxic T lymphocytes and is often overexpressed in cancers. Due to favorable clinical trial results, immune checkpoint inhibition (ICI) is now part of Food and Drug Administration-approved immuno-oncology therapies; however, not all patients derive benefit from ICI therapy. High blood platelet-to-lymphocyte ratio has been associated with failure of ICI treatment, but whether platelets have a role in hindering ICI response is not clear. Here, we report that co-culturing platelets with breast and lung Cancer cell lines increased protein and gene expression of tumor cell PD-L1. Platelet-induced tumor cell PD-L1 upregulation was reduced by anti-platelet agents, such as aspirin and ticagrelor. Platelet cytokine arrays revealed that the well-established cytokines, including interferon-gamma, were not the main regulators of platelet-mediated PD-L1 upregulation. Instead, the high molecular weight epidermal growth factor (HWM-EGF) is abundant in platelets, which caused an upregulation of tumor cell PD-L1. Both an EGF neutralizing antibody and the drug, Cetuximab (EGF-receptor neutralizing antibody) inhibited platelet-induced increases in tumor cell PD-L1, suggesting that platelets induce tumor cell PD-L1 in an EGFR-dependent manner. Our data reveal a novel mechanism for platelets in tumor immune escape and warrant further investigation to determine if targeting platelets improves ICI therapeutic responses.