We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
A small-molecule P2RX7 activator promotes anti-tumor immune responses and sensitizes lung tumor to immunotherapy.
- Authors
Douguet, Laetitia; Janho dit Hreich, Serena; Benzaquen, Jonathan; Seguin, Laetitia; Juhel, Thierry; Dezitter, Xavier; Duranton, Christophe; Ryffel, Bernhard; Kanellopoulos, Jean; Delarasse, Cecile; Renault, Nicolas; Furman, Christophe; Homerin, Germain; Féral, Chloé; Cherfils-Vicini, Julien; Millet, Régis; Adriouch, Sahil; Ghinet, Alina; Hofman, Paul; Vouret-Craviari, Valérie
- 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. A limited percentage of patients with non-small cell lung cancer respond to immunotherapy. Here the authors show that HEI3090, a chemical positive modulator of the purinergic P2RX7 receptor, promotes IL-18 mediated anti-tumor immune responses and sensitizes lung cancer to anti-PD-1 therapy in preclinical models.
- Subjects
IMMUNE response; LUNG tumors; NON-small-cell lung carcinoma; IMMUNE checkpoint inhibitors; CYTOTOXIC T cells; GLUTAMATE receptors; PROGRAMMED cell death 1 receptors
- Publication
Nature Communications, 2021, Vol 12, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-021-20912-2