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

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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Submitted on : Monday, February 1, 2021 - 11:19:50 AM
Last modification on : Sunday, May 1, 2022 - 3:17:15 AM
Long-term archiving on: : Sunday, May 2, 2021 - 6:58:49 PM


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Laetitia Douguet, Serena Janho Dit Hreich, Jonathan Benzaquen, Laetitia Seguin, Thierry Juhel, et al.. A small-molecule P2RX7 activator promotes anti-tumor immune responses and sensitizes lung tumor to immunotherapy. Nature Communications, Nature Publishing Group, 2021, 12 (1), pp.653. ⟨10.1038/s41467-021-20912-2⟩. ⟨hal-03126997⟩



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