High Expression of MHC Class I Overcomes Cancer Immunotherapy Resistance Due to IFNγ Signaling Pathway Defects

Cancer Immunol Res. 2023 Jul 5;11(7):895-908. doi: 10.1158/2326-6066.CIR-22-0815.


IFNγ signaling pathway defects are well-known mechanisms of resistance to immune checkpoint inhibitors. However, conflicting data have been reported, and the detailed mechanisms remain unclear. In this study, we have demonstrated that resistance to immune checkpoint inhibitors owing to IFNγ signaling pathway defects may be primarily caused by reduced MHC-I expression rather than by the loss of inhibitory effects on cellular proliferation or decreased chemokine production. In particular, we found that chemokines that recruit effector T cells were mainly produced by immune cells rather than cancer cells in the tumor microenvironment of a mouse model, with defects in IFNγ signaling pathways. Furthermore, we found a response to immune checkpoint inhibitors in a patient with JAK-negative head and neck squamous cell carcinoma whose HLA-I expression level was maintained. In addition, CRISPR screening to identify molecules associated with elevated MHC-I expression independent of IFNγ signaling pathways demonstrated that guanine nucleotide-binding protein subunit gamma 4 (GNG4) maintained MHC-I expression via the NF-κB signaling pathway. Our results indicate that patients with IFNγ signaling pathway defects are not always resistant to immune checkpoint inhibitors and highlight the importance of MHC-I expression among the pathways and the possibility of NF-κB-targeted therapies to overcome such resistance. See related Spotlight by Haugh and Daud, p. 864.

Publication types

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

MeSH terms

  • Animals
  • Head and Neck Neoplasms*
  • Immune Checkpoint Inhibitors*
  • Immunotherapy / methods
  • Interferon-gamma / metabolism
  • Mice
  • NF-kappa B / metabolism
  • Signal Transduction / drug effects
  • Tumor Microenvironment / drug effects


  • Immune Checkpoint Inhibitors
  • NF-kappa B
  • Interferon-gamma