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.

doi:10.1101/2020.11.19.388900

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bioRxiv · 10.1101/2020.11.19.388900

Small-molecule P2RX7 activator sensitizes tumor to immunotherapy and vaccinates mouse against tumor re-challenge

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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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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.. 2020-11-20. Small-molecule P2RX7 activator sensitizes tumor to immunotherapy and vaccinates mouse against tumor re-challenge. https://doi.org/10.1101/2020.11.19.388900

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