PT  - JOURNAL ARTICLE
AU  - Laetitia Douguet
AU  - Serena Janho dit Hreich
AU  - Jonathan Benzaquen
AU  - Laetitia Seguin
AU  - Thierry Juhel
AU  - Xavier Dezitter
AU  - Christophe Duranton
AU  - Bernhard Ryffel
AU  - Jean Kanellopoulos
AU  - Cecile Delarasse
AU  - Nicolas Renault
AU  - Christophe Furman
AU  - Germain Homerin
AU  - Chloé Féral
AU  - Julien Cherfils-Vicini
AU  - Régis Millet
AU  - Sahil Adriouch
AU  - Alina Ghinet
AU  - Paul Hofman
AU  - Valérie Vouret-Craviari
TI  - Small-molecule P2RX7 activator sensitizes tumor to immunotherapy and vaccinates mouse against tumor re-challenge
AID  - 10.1101/2020.11.19.388900
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.11.19.388900
4099  - http://biorxiv.org/content/early/2020/11/20/2020.11.19.388900.short
4100  - http://biorxiv.org/content/early/2020/11/20/2020.11.19.388900.full
AB  - 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 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 promising novel strategy that may be active against NSCLC.Competing Interest StatementThe authors have declared no competing interest.