Fiche publication
Date publication
novembre 2025
Journal
Nature communications
Auteurs
Membres identifiés du Cancéropôle Est :
Pr GHIRINGHELLI François
,
Mme TRUNTZER Caroline
,
Dr REBE Cédric
,
Dr CHALMIN Fanny
,
Dr LIMAGNE Emeric
,
Dr DERANGERE Valentin
,
Dr AUCAGNE Romain
,
Dr BELLIO Hélène
Tous les auteurs :
Perrichet A, Lecuelle J, Limagne E, Thiefin M, Bellio H, Jacob P, Aucagne R, Aznague A, Russo P, Gaucher F, Roussot N, Yang X, Vernet T, Nuttin L, Ilie A, Rageot D, Derangère V, Huppe T, Zippelius A, Routy B, Truntzer C, Chalmin F, Ghiringhelli F, Rébé C
Lien Pubmed
Résumé
Many non-small cell lung cancer (NSCLC) patients remain unresponsive to the current standard of care, which includes chemotherapy and immune checkpoint inhibitors, like anti-PD-1/PD-L1 antibodies. While interleukin (IL)-1β is known to promote lung cancer growth in humans and mice, we show here that IL-1β administration or overexpression overcomes resistance to classical chemo-immunotherapy (cisplatin/pemetrexed/anti-PD-1) in mouse lung cancer models. The antitumor effects of IL-1β rely on cancer cell-derived CXCL10 which mediates CD8 T cell recruitment at the tumor site. In lung cancer cells, Thioredoxin Interacting Protein (TXNIP) induces mitochondrial DNA (mtDNA) release in the cytosol, activating Absence in Melanoma 2 (AIM2) inflammasome, which subsequently triggers IL-1β and CXCL10 secretion, thereby reversing chemo-immunotherapy resistance. The clinical relevance of our findings is supported by the transcriptomic analysis of patient tumors, showing that high expression of IL1B, IL1R1, AIM2 and/or TXNIP is associated with better response to immunotherapy in NSCLC patients. Additionally, drug screening identifies MEK and MDM2 inhibitors as inducers of TXNIP expression capable of reversing resistance to chemo-immunotherapy. This study highlights a positive role of IL-1β in lung cancer treatment and suggests that enhancing IL-1β production at the tumor site can overcome resistance to chemo-immunotherapy.
Mots clés
Carcinoma, Non-Small-Cell Lung, drug therapy, Animals, Lung Neoplasms, drug therapy, Humans, Interleukin-1beta, metabolism, Drug Resistance, Neoplasm, genetics, Mice, Cell Line, Tumor, Chemokine CXCL10, metabolism, Carrier Proteins, metabolism, Immunotherapy, methods, Cisplatin, pharmacology, DNA-Binding Proteins, metabolism, Inflammasomes, metabolism, Pemetrexed, pharmacology, Female, CD8-Positive T-Lymphocytes, immunology, Immune Checkpoint Inhibitors, pharmacology
Référence
Nat Commun. 2025 11 21;16(1):10244
