Small-molecule P2RX7 activator sensitizes tumor to immunotherapy and vaccinates mouse against tumor re-challenge
Douguet, L.; Janho dit hreich, S.; Benzaquen, J.; seguin, l.; Juhel, T.; Dezitter, X.; Duranton, C.; Ryffel, B.; Kanellopoulos, J.; Delarasse, C.; Renault, N.; Furman, C.; Homerin, G.; Feral, C.; Cherfils-Vicini, J.; Millet, R.; Adriouch, S.; Ghinet, A.; Hofman, P.; Vouret-Craviari, V.
Show abstract
Only a subpopulation of non-small cell lung cancer (NSCLC) patients responds to immunotherapies, highlighting the urgent need to develop new therapeutic strategies to improve patient outcome. We developed a new chemical positive modulator (HEI3090) of the purinergic P2RX7 receptor that potentiates PD-1 treatment to effectively control the growth of lung tumors in transplantable and oncogene-induced mouse models and triggers long lasting antitumor immune responses. Mechanistically, the molecule stimulates dendritic P2RX7 expressing cells to generate IL-18 which leads to the production of IFN-{gamma} by Natural Killer and CD4+ T cells within tumors. Combined with immune checkpoint inhibitor, the molecule induces a complete tumor regression in 80% of LLC tumor bearing mice. Cured mice are also protected against tumor re-challenge due to a CD8-dependent protective response. Hence, combination treatment of small-molecule P2RX7 activator followed by immune checkpoint inhibitor represents a promising novel strategy that may be active against NSCLC.
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