Endothelial PD-L1 brakes CD8+ T cell exhaustion, empowering anti-tumor immunity in non-small cell lung cancer

Cancer immunotherapies targeting PD-(L)1 offer therapeutic potential but suffer resistance. The role of PD-L1 in tumor and myeloid cells has been extensively studied, while its function in tumor endothelial cells (ECs) is overlooked. Surprisingly, we identified an unknown role of EC-specific PD-L1 in delaying the exhaustion of tumor-infiltrating CD8+ T cells in a non-small cell lung cancer mouse model. Loss of endothelial PD-L1 reduces T cell activation and exac-erbates tumor growth. Initial inhibition of CD8+ T cells by endothelial PD-L1, prior to encoun-tering cancer cells, prevents T cells from prematurely reaching a terminal exhaustion state. Initial results suggest that high EC PD-L1 expression in NSCLC patient tumors might become a potential positive predictor of anti-PD-1 outcome. These unexpected findings highlight the significance of vessel-associated PD-L1 and suggest that EC PD-L1 blockade upon systemic treatment potentially negates the overall therapeutic effect, raising the question if this might contribute to therapy resistance.