作者: Vouret-Craviari, Valerie ; Juhel, Thierry ; Brau, Frederic ; Janho dit Hreich, Serena ; Hofman, Veronique ; Ghinet, Alina ; Leroy, Sylvie ; Hofman, Paul

Idiopathic pulmonary fibrosis (IPF) is an aggressive interstitial lung disease associated with progressive and irreversible deterioration of respiratory functions that lacks curative therapies. Despite IPF being associated with a dysregulated immune response, current antifibrotics aim only at limiting fibroproliferation. Transcriptomic analyses show that the P2RX7/IL18/IFNG axis is downregulated in IPF patients and that P2RX7 has immunoregulatory functions. Using our positive modulator of P2RX7, we show that activation of the P2RX7/IL-18 axis in immune cells limits lung fibrosis progression in a mouse model by favoring an antifibrotic immune environment, with notably an enhanced IL-18-dependent IFN-γ production by lung T cells leading to a decreased production of IL-17 and TGFβ. Overall, we show the ability of the immune system to limit lung fibrosis progression by targeting the immunomodulator P2RX7. Hence, treatment with a small activator of P2RX7 may represent a promising strategy to help patients with lung fibrosis.

Nature Communications1区 · 综合性期刊

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

1区 · 综合性期刊

ArticleOA

作者: Adriouch, Sahil ; Juhel, Thierry ; Benzaquen, Jonathan ; Cherfils-Vicini, Julien ; Millet, Régis ; Janho Dit Hreich, Serena ; Ghinet, Alina ; Douguet, Laetitia ; Kanellopoulos, Jean ; Vouret-Craviari, Valérie ; Homerin, Germain ; Ryffel, Bernhard ; Seguin, Laetitia ; Dezitter, Xavier ; Delarasse, Cecile ; Hofman, Paul ; Renault, Nicolas ; Duranton, Christophe ; Féral, Chloé ; Furman, Christophe

AbstractOnly 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.

100 项与 HEI3090 相关的药物交易

登录后查看更多信息