A small-molecule P2RX7 activator promotes anti-tumor immune responses and sensitizes lung tumor to immunotherapy
Laëtitia Douguet, Séréna Janho dit Hreich, Jonathan Benzaquen, Laetitia Seguin, Thierry Juhel, Xavier Dezitter, Christophe Duranton, Bernhard Ryffel, Jean Kanellopoulos, Cécile Delarasse, Nicolas Renault, Christophe Furman, Germain Homerin, Chloé C. Féral, Julien Cherfils‐Vicini, Régis Millet, Sahil Adriouch, Alina Ghinet, Paul Hofman, Valérie Vouret‐Craviari
Abstract
Abstract Only a subpopulation of non-small cell lung cancer (NSCLC) patients responds to immunotherapies, highlighting the urgent need to develop therapeutic strategies to improve patient outcome. We develop a chemical positive modulator (HEI3090) of the purinergic P2RX7 receptor that potentiates αPD-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-γ 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 strategy that may be active against NSCLC.