A small-molecule P2RX7 activator promotes anti-tumor immune responses and sensitizes lung tumor to immunotherapy

Laetitia Douguet (), Serena Janho dit Hreich, Jonathan Benzaquen, Laetitia Seguin, Thierry Juhel, Xavier Dezitter, Christophe Duranton, Bernhard Ryffel, Jean Kanellopoulos, Cecile Delarasse, Nicolas Renault, Christophe Furman, Germain Homerin, Chloé Féral, Julien Cherfils-Vicini, Régis Millet, Sahil Adriouch, Alina Ghinet, Paul Hofman and Valérie Vouret-Craviari ()
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Laetitia Douguet: Université Côte d’Azur, CNRS, INSERM, IRCAN
Serena Janho dit Hreich: Université Côte d’Azur, CNRS, INSERM, IRCAN
Jonathan Benzaquen: Université Côte d’Azur, CNRS, INSERM, IRCAN
Laetitia Seguin: Université Côte d’Azur, CNRS, INSERM, IRCAN
Thierry Juhel: Université Côte d’Azur, CNRS, INSERM, IRCAN
Xavier Dezitter: Inserm, CHU Lille, U1286—Infinite—Institute for Translational Research in Inflammation, University of Lille
Christophe Duranton: Université Côte d’Azur, CNRS, INSERM, LP2M
Bernhard Ryffel: INEM—UMR7355, Institute of Molecular Immunology and Neurogenetic, University and CNRS
Jean Kanellopoulos: CEA, CNRS, Université Paris-Saclay
Cecile Delarasse: INSERM, CNRS, Institut de la Vision, Sorbonne Université
Nicolas Renault: Inserm, CHU Lille, U1286—Infinite—Institute for Translational Research in Inflammation, University of Lille
Christophe Furman: Inserm, CHU Lille, U1286—Infinite—Institute for Translational Research in Inflammation, University of Lille
Germain Homerin: Inserm, CHU Lille, U1286—Infinite—Institute for Translational Research in Inflammation, University of Lille
Chloé Féral: Université Côte d’Azur, CNRS, INSERM, IRCAN
Julien Cherfils-Vicini: Université Côte d’Azur, CNRS, INSERM, IRCAN
Régis Millet: Inserm, CHU Lille, U1286—Infinite—Institute for Translational Research in Inflammation, University of Lille
Sahil Adriouch: Institute for Research and Innovation in Biomedicine, Normandie University
Alina Ghinet: Inserm, CHU Lille, U1286—Infinite—Institute for Translational Research in Inflammation, University of Lille
Paul Hofman: Université Côte d’Azur, CNRS, INSERM, IRCAN
Valérie Vouret-Craviari: Université Côte d’Azur, CNRS, INSERM, IRCAN

Nature Communications, 2021, vol. 12, issue 1, 1-17

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.

Date: 2021
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DOI: 10.1038/s41467-021-20912-2

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