CRI INSERM UMR1231 "Lipids, Nutrition and Cancer," Team "CAdIR," Dijon, Burgundy, France.
Faculté des Sciences de Santé, Université Bourgogne Franche-Comté, Dijon, Burgundy, France.
Cancer Immunol Res. 2021 Mar;9(3):324-336. doi: 10.1158/2326-6066.CIR-19-0679. Epub 2021 Jan 8.
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 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.
免疫系统显然可以影响癌症对治疗的反应。然而，肿瘤微环境（TME）对免疫细胞的影响还不完全清楚。在这方面，越来越多的证据表明选择性剪接会影响免疫系统。在这里，我们表明 TME 通过 TGFβ 依赖性机制增加了选择性剪接事件，并诱导 Th1 细胞中 IRF1 转录因子（IRF1Δ7）的一种替代异构体的表达。我们发现 SFPQ 剪接因子（富含脯氨酸和谷氨酸的剪接因子）负责产生 IRF1Δ7。我们还在小鼠和人类中表明，IRF1 替代异构体改变了全长 IRF1 在启动子上的转录活性，导致 Th1 细胞中 IFNγ 的分泌减少。因此，IRF1Δ7 异构体在 TME 中增加，抑制 IRF1Δ7 的表达可以增强 Th1 抗肿瘤反应。
