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

Author

Listed:
  • Laetitia Douguet

    (Université Côte d’Azur, CNRS, INSERM, IRCAN)

  • Serena Janho dit Hreich

    (Université Côte d’Azur, CNRS, INSERM, IRCAN
    FHU OncoAge
    Centre Antoine Lacassagne)

  • Jonathan Benzaquen

    (Université Côte d’Azur, CNRS, INSERM, IRCAN
    FHU OncoAge
    Centre Antoine Lacassagne)

  • Laetitia Seguin

    (Université Côte d’Azur, CNRS, INSERM, IRCAN
    FHU OncoAge)

  • 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
    Institut de Chimie Pharmaceutique Albert Lespagnol, IFR114)

  • 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
    Institut de Chimie Pharmaceutique Albert Lespagnol, IFR114)

  • Christophe Furman

    (Inserm, CHU Lille, U1286—Infinite—Institute for Translational Research in Inflammation, University of Lille
    Institut de Chimie Pharmaceutique Albert Lespagnol, IFR114)

  • Germain Homerin

    (Inserm, CHU Lille, U1286—Infinite—Institute for Translational Research in Inflammation, University of Lille
    Hautes Etudes d’Ingénieur (HEI), JUNIA, UC Lille, Laboratoire de Chimie Durable et Santé)

  • Chloé Féral

    (Université Côte d’Azur, CNRS, INSERM, IRCAN
    FHU OncoAge)

  • 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
    Institut de Chimie Pharmaceutique Albert Lespagnol, IFR114)

  • 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
    Hautes Etudes d’Ingénieur (HEI), JUNIA, UC Lille, Laboratoire de Chimie Durable et Santé
    ‘Al. I. Cuza’ University of Iasi)

  • Paul Hofman

    (Université Côte d’Azur, CNRS, INSERM, IRCAN
    FHU OncoAge
    Hospital-Related Biobank (BB-0033-00025), Pasteur Hospital
    Laboratory of Clinical and Experimental Pathology and Biobank, Pasteur Hospital)

  • Valérie Vouret-Craviari

    (Université Côte d’Azur, CNRS, INSERM, IRCAN
    FHU OncoAge
    Centre Antoine Lacassagne)

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.

Suggested Citation

  • Laetitia Douguet & Serena Janho dit Hreich & Jonathan Benzaquen & Laetitia Seguin & Thierry Juhel & Xavier Dezitter & Christophe Duranton & Bernhard Ryffel & Jean Kanellopoulos & Cecile Delarasse & Ni, 2021. "A small-molecule P2RX7 activator promotes anti-tumor immune responses and sensitizes lung tumor to immunotherapy," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-20912-2
    DOI: 10.1038/s41467-021-20912-2
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