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

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

  • Nat Commun. 2021 Jan 28;12(1):653. doi: 10.1038/s41467-021-20912-2.
Laetitia Douguet # 1,  Serena Janho Dit Hreich # 2 3 4,  Jonathan Benzaquen 2 3 4,  Laetitia Seguin 2 3,  Thierry Juhel 2,  Xavier Dezitter 5 6,  Christophe Duranton 7,  Bernhard Ryffel 8,  Jean Kanellopoulos 9,  Cecile Delarasse 10,  Nicolas Renault 5 6,  Christophe Furman 5 6,  Germain Homerin 5 11,  Chloé Féral 2 3,  Julien Cherfils-Vicini 2,  Régis Millet 5 6,  Sahil Adriouch 12,  Alina Ghinet 5 11 13,  Paul Hofman 2 3 14 15,  Valérie Vouret-Craviari 16 17 18
Affiliations

Affiliations

  • 1 Université Côte d'Azur, CNRS, INSERM, IRCAN, Nice, France. ldouguet@gmail.com.
  • 2 Université Côte d'Azur, CNRS, INSERM, IRCAN, Nice, France.
  • 3 FHU OncoAge, Nice, France.
  • 4 Centre Antoine Lacassagne, Nice, France.
  • 5 Inserm, CHU Lille, U1286-Infinite-Institute for Translational Research in Inflammation, University of Lille, Lille, France.
  • 6 Institut de Chimie Pharmaceutique Albert Lespagnol, IFR114, Lille, France.
  • 7 Université Côte d'Azur, CNRS, INSERM, LP2M, Nice, France.
  • 8 INEM-UMR7355, Institute of Molecular Immunology and Neurogenetic, University and CNRS, Orleans, France.
  • 9 Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Université Paris-Saclay, Gif-sur-Yvette Cedex, France.
  • 10 INSERM, CNRS, Institut de la Vision, Sorbonne Université, Paris, France.
  • 11 Hautes Etudes d'Ingénieur (HEI), JUNIA, UC Lille, Laboratoire de Chimie Durable et Santé, Lille, France.
  • 12 Institute for Research and Innovation in Biomedicine, Normandie University, Rouen, France.
  • 13 Faculty of Chemistry, 'Al. I. Cuza' University of Iasi, Iasi, Romania.
  • 14 Hospital-Related Biobank (BB-0033-00025), Pasteur Hospital, Nice, France.
  • 15 Laboratory of Clinical and Experimental Pathology and Biobank, Pasteur Hospital, Nice, France.
  • 16 Université Côte d'Azur, CNRS, INSERM, IRCAN, Nice, France. valerie.vouret@univ-cotedazur.fr.
  • 17 FHU OncoAge, Nice, France. valerie.vouret@univ-cotedazur.fr.
  • 18 Centre Antoine Lacassagne, Nice, France. valerie.vouret@univ-cotedazur.fr.
  • # Contributed equally.
PMID: 33510147 DOI: 10.1038/s41467-021-20912-2
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.

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