The Tumor Microenvironment Impairs Th1 IFNγ Secretion through Alternative Splicing Modifications of Irf1 Pre-mRNA

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 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.

Publication types

  • Observational Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing
  • Animals
  • Cell Line, Tumor
  • Disease Models, Animal
  • Gene Expression Regulation, Neoplastic / immunology
  • Gene Knockdown Techniques
  • Humans
  • Interferon Regulatory Factor-1 / genetics*
  • Interferon Regulatory Factor-1 / metabolism
  • Interferon-gamma / metabolism*
  • Mice
  • Neoplasms / genetics
  • Neoplasms / immunology*
  • Neoplasms / pathology
  • Promoter Regions, Genetic
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • RNA Precursors / metabolism
  • RNA, Messenger / metabolism
  • RNA-Seq
  • Receptors, Interleukin-12
  • Th1 Cells / immunology
  • Th1 Cells / metabolism
  • Tumor Escape / genetics
  • Tumor Microenvironment / genetics
  • Tumor Microenvironment / immunology


  • IFNG protein, human
  • IFNG protein, mouse
  • IL12RB1 protein, human
  • IRF1 protein, human
  • Il12rb1 protein, mouse
  • Interferon Regulatory Factor-1
  • Irf1 protein, mouse
  • Protein Isoforms
  • RNA Precursors
  • RNA, Messenger
  • Receptors, Interleukin-12
  • Interferon-gamma