Funding
Japan Society for the Promotion of Science (JSPS)
Japan Agency for Medical Research and Development (AMED)
Fusion Oriented REsearch for disruptive Science and Technology (FOREST)
Naito Foundation (内藤記念科学振興財団)
Takeda Science Foundation (TSF)
Mochida Memorial Foundation for Medical and Pharmaceutical Research (公益財団法人 持田記念医学薬学振興財団)
Japanese Foundation for Multidisciplinary Treatment of Cancer Foundation
MSD Life Science Foundation, Public Interest Incorporated Foundation (SD Life Science Foundation)
Senri Life Science Foundation
GSK Japan Research Grant 2021
Japanese Respiratory Foundation (JRF)
Princess Takamatsu Cancer Research Fund
Kato Memorial Bioscience Foundation
Ono Medical Research Foundation
Inamori Foundation
Ube Foundation
Wesco Science Foundation (公益財団法人ウエスコ学術振興財団)
ARTICLE ABSTRACT
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
