Abstract 707: High major histocompatibility complex class I expression overcomes cancer immunotherapy resistance due to interferon gamma signaling pathway defects

Abstract IFN-γ signaling pathway defects such as JAK mutations are well-known mechanisms of resistance to immune checkpoint inhibitors (ICIs). However, some patients respond to ICIs despite IFN-γ signaling pathway defects, and the detailed mechanisms remain unclear. Here, we created JAK-deleted cancer cell lines and evaluated antitumor immunity. As a result, several tumors responded to PD-1 blockade despite JAK deletion. Such sensitive tumors had high major histocompatibility complex class I (MHC-I) expression despite IFN-γ signaling pathway defects, whereas MHC-I expression was reduced by JAK deletion in resistant tumors. In particular, if cancer cells had high MHC-I expression despite defects in IFN-γ signaling pathways, chemokines that recruit effector T cells were mainly produced by immune cells rather than cancer cells in the tumor microenvironment. Accordingly, we found a response to ICIs in a patient with JAK-negative head and neck squamous cell carcinoma, whose human leukocyte antigen class I (HLA-I) expression level was maintained. In addition, clustered regularly interspaced short palindromic repeats (CRISPR) screening to identify molecules with elevated MHC-I expression independent of IFN-γ 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 IFN-ɤ signaling pathway defects are not always resistant to ICIs, and highlight the importance of MHC-I expression among the pathways, including inhibitory effects on cellular proliferation or chemokine production, and the possibility of NF-κB-targeted therapies to overcome such resistance. Citation Format: Katsushige Kawase, Shusuke Kawashima, Joji Nagasaki, Takashi Inozume, Hiromasa Yamamoto, Masahito Kawazu, Toyoyuki Hanazawa, Yosuke Togashi. High major histocompatibility complex class I expression overcomes cancer immunotherapy resistance due to interferon gamma signaling pathway defects [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 707.