Effect of PD-1/PD-L1 immune checkpoint blockade on NK cell-mediated anti-tumor immune response

Hypoxia, a common feature of the tumor microenvironment, plays a major role in solid tumor survival and progression. Our previous works have clearly identified a direct link between hypoxic tumor microenvironment and immune evasion from Natural Killer (NK) cells-mediated killing. We provided evidence that even fully effective NK-mediated antitumor immune response, cancer cells under hypoxic stress can outmaneuver functional immune system by activating intrinsic resistance mechanisms involving autophagy. Anticancer immunotherapies allowing the reactivation of the immune system, through blockade of PD1/PD-L1 axis, have shown promising results on overall survival in patients with advanced melanomas. However, the use of such strategies based on solely boosting or reactivating the immune cells, without considering resistance mechanisms that could operate in tumor cells would be probably not sufficient. So far, little attention have been paid to examine the role of the PD-1/PD-L1 checkpoint in the regulation of the NK cells-mediated antitumor response which constitute and integral part of the tumor immunosurveillance. Therefore, the aim of this project is to investigate 1) the implication of the PD-1/PD-L1 checkpoint in the NK cells-mediated antitumor response, 2) the influence of hypoxic stress, and more particularly hypoxia-induced autophagy, on the development of intrinsic resistance mechanisms involving the upregulation of the inhibitory ligand PD-L1, and 3) the therapeutic relevance of the use of autophagy and PD-1/PD-L1 inhibitors combinations. This project will provide further insight into the molecular mechanisms sustaining the resistance of certain hypoxic tumor cells to NK cells-mediated lysis. Furthermore, it will provide new perspective for the development of innovative immunotherapeutic approaches for cancer treatment.