A small-molecule P2RX7 activator promotes anti-tumor immune responses and sensitizes lung tumor to immunotherapy - Sorbonne Université Access content directly
Journal Articles Nature Communications Year : 2021

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

Cécile Delarasse

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.
Fichier principal
Vignette du fichier
s41467-021-20912-2.pdf (4.78 Mo) Télécharger le fichier
Origin : Publication funded by an institution

Dates and versions

hal-03126997 , version 1 (01-02-2021)

Licence

Attribution

Identifiers

Cite

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, 2021, 12 (1), p.653. ⟨10.1038/s41467-021-20912-2⟩. ⟨hal-03126997⟩
410 View
96 Download

Altmetric

Share

Gmail Facebook X LinkedIn More