The tumor microenvironment impairs Th1 IFNγ secretion through alternative splicing modifications of Irf1 pre-mRNA.

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Date publication

janvier 2021


Cancer immunology research


Membres identifiés du Cancéropôle Est :
Pr BERNARD Alain, Dr BOIDOT Romain, Pr GHIRINGHELLI François, Dr HERVOUET Eric, Dr PEIXOTO Paul, Dr VEGRAN Frédérique, Dr BRUCHARD Mélanie, Dr CHALMIN Fanny

Tous les auteurs :
Bernard A, Hibos C, Richard C, Viltard E, Chevrier S, Lemoine S, Melin J, Humblin E, Mary R, Accogli T, Chalmin F, Bruchard M, Peixoto P, Hervouet E, Apetoh L, Ghiringhelli F, Vegran F, Boidot R


It is clearly established that immune system can affect cancer response to therapy. However, the influence of the tumor microenvironment on immune cells is not completely understood. In this respect, alternative splicing is increasingly described to affect the immune system. Here, we showed that the tumor microenvironment, via a TGFβ-dependent mechanism, increased alternative splicing events and induced the expression of an alternative isoform of the IRF1 transcription factor (IRF1Δ7) in Th1 cells. We found that the SFPQ splicing factor was responsible for the IRF1Δ7 production. We also showed, in both mice and humans, that the IRF1 alternative isoform altered the full-length IRF1 transcriptional activity on the Il12rb1 promotor, resulting in decreased IFNγ secretion in Th1 cells. Thus, the IRF1Δ7 isoform was increased in the tumor microenvironment, and inhibiting IRF1Δ7 expression could potentiate Th1 antitumor responses.


Cancer Immunol Res. 2021 Jan 8;: