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
  • 1. Université Côte d'Azur, CNRS, INSERM, IRCAN, Nice, France. [email protected].
  • 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. [email protected].
  • 17. FHU OncoAge, Nice, France. [email protected].
  • 18. Centre Antoine Lacassagne, Nice, France. [email protected].
  • # 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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