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

IFNy signaling pathway defects are well-known mechanisms of resistance to immune checkpoint inhibitors. However, con-flicting data have been reported, and the detailed mechanisms remain unclear. In this study, we have demonstrated that resis-tance to immune checkpoint inhibitors owing to IFNy 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 IFNy 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 IFNy signaling pathways demonstrated that guanine nucleotide-binding protein subunit gamma 4 (GNG4) maintained MHC-I expression via the NF-1cB signaling pathway. Our results indicate that patients with IFNy 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-1cB- targeted therapies to overcome such resistance.See related Spotlight by Haugh and Daud, p. 864