Frequent Loss of IRF2 in Cancers Leads to Immune Evasion through Decreased MHC Class I Antigen Presentation and Increased PD-L1 Expression

J Immunol. 2019 Oct 1;203(7):1999-2010. doi: 10.4049/jimmunol.1900475. Epub 2019 Aug 30.


To arise and progress, cancers need to evade immune elimination. Consequently, progressing tumors are often MHC class I (MHC-I) low and express immune inhibitory molecules, such as PD-L1, which allows them to avoid the main antitumor host defense, CD8+ T cells. The molecular mechanisms that led to these alterations were incompletely understood. In this study, we identify loss of the transcription factor IRF2 as a frequent underlying mechanism that leads to a tumor immune evasion phenotype in both humans and mice. We identified IRF2 in a CRISPR-based forward genetic screen for genes that controlled MHC-I Ag presentation in HeLa cells. We then found that many primary human cancers, including lung, colon, breast, prostate, and others, frequently downregulated IRF2. Although IRF2 is generally known as a transcriptional repressor, we found that it was a transcriptional activator of many key components of the MHC-I pathway, including immunoproteasomes, TAP, and ERAP1, whose transcriptional control was previously poorly understood. Upon loss of IRF2, cytosol-to-endoplasmic reticulum peptide transport and N-terminal peptide trimming become rate limiting for Ag presentation. In addition, we found that IRF2 is a repressor of PD-L1. Thus, by downregulating a single nonessential gene, tumors become harder to see (reduced Ag presentation), more inhibitory (increased checkpoint inhibitor), and less susceptible to being killed by CD8+ T cells. Importantly, we found that the loss of Ag presentation caused by IRF2 downregulation could be reversed by IFN-stimulated induction of the transcription factor IRF1. The implication of these findings for tumor progression and immunotherapy are discussed.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigen Presentation*
  • B7-H1 Antigen / genetics
  • B7-H1 Antigen / immunology*
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / pathology
  • Down-Regulation / immunology
  • Gene Expression Regulation, Neoplastic / immunology
  • HEK293 Cells
  • HeLa Cells
  • Histocompatibility Antigens Class I / genetics
  • Histocompatibility Antigens Class I / immunology*
  • Humans
  • Interferon Regulatory Factor-2 / deficiency*
  • Interferon Regulatory Factor-2 / immunology
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / immunology*
  • Neoplasms* / genetics
  • Neoplasms* / immunology
  • Neoplasms* / pathology
  • Tumor Escape*


  • B7-H1 Antigen
  • CD274 protein, human
  • Histocompatibility Antigens Class I
  • IRF2 protein, human
  • Interferon Regulatory Factor-2
  • Neoplasm Proteins