The Tumor Microenvironment Impairs Th1 IFNγ Secretion through Alternative Splicing Modifications of <i>Irf1</i> Pre-mRNA
Antoine Bernard, Christophe Hibos, Corentin Richard, Etienne Viltard, Sandy Chevrier, Sophie Lemoine, Joséphine Melin, Étienne Humblin, Romain Mary, Théo Accogli, Fanny Chalmin, Mélanie Bruchard, Paul Peixoto, Éric Hervouet, Lionel Apétoh, François Ghiringhelli, Frédérique Végran, Romain Boidot
Abstract
Abstract It is clearly established that the immune system can affect cancer response to therapy. However, the influence of the tumor microenvironment (TME) 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 TME, 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 (splicing factor, proline- and glutamine-rich) 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 promoter, resulting in decreased IFNγ secretion in Th1 cells. Thus, the IRF1Δ7 isoform was increased in the TME, and inhibiting IRF1Δ7 expression could potentiate Th1 antitumor responses.