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

Laetitia Douguet1, Serena Janho Dit Hreich2,3,4, Jonathan Benzaquen2,3,4

  • 1Université Côte d'Azur, CNRS, INSERM, IRCAN, Nice, France. ldouguet@gmail.com.

Nature Communications
|January 29, 2021
PubMed

Insights

A novel P2RX7 receptor activator, HEI3090, combined with αPD-1 immunotherapy, effectively controls non-small cell lung cancer (NSCLC) growth and triggers lasting immune responses in preclinical models.

Area of Science:

  • Immunology
  • Oncology
  • Pharmacology

Background:

  • Limited response rates to current immunotherapies in non-small cell lung cancer (NSCLC) necessitate novel therapeutic strategies.
  • Targeting the purinergic P2RX7 receptor presents a potential avenue for enhancing anti-tumor immunity.

Purpose of the Study:

  • To investigate the efficacy of a novel P2RX7 receptor positive modulator (HEI3090) in combination with αPD-1 immunotherapy for NSCLC treatment.
  • To elucidate the underlying mechanisms of action for the combined therapeutic approach.

Main Methods:

  • Development of a chemical positive modulator (HEI3090) for the purinergic P2RX7 receptor.
  • Evaluation of HEI3090 in combination with αPD-1 treatment in transplantable and oncogene-induced mouse models of NSCLC.
  • Assessment of immune cell activation, cytokine production (IL-18, IFN-γ), and tumor regression.

Main Results:

  • HEI3090 potentiated αPD-1 treatment, leading to effective control of lung tumor growth in mouse models.
  • The combination therapy stimulated P2RX7-expressing dendritic cells to produce IL-18, enhancing IFN-γ production by Natural Killer and CD4+ T cells.
  • Complete tumor regression was observed in 80% of LLC tumor-bearing mice, with cured mice exhibiting CD8-dependent protection against tumor re-challenge.

Conclusions:

  • Combination treatment with a small-molecule P2RX7 activator and an immune checkpoint inhibitor shows significant promise for NSCLC therapy.
  • This strategy induces durable anti-tumor immune responses and may overcome resistance to current immunotherapies.

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