IGSF8 is an innate immune checkpoint and cancer immunotherapy target

• DOI: 10.1016/j.cell.2024.03.039
• Publication Date: 2024-04-23T14:34:48Z
• Authors: Yulong Li; Xiangyang Wu; Caibin Sheng; Hailing Liu; Huizhu Liu; Yixuan Tang; Chao Liu; Qingyang Ding; Bin Xie; Xi Xiao; Rongbin Zheng; Quan Yu; Zengdan Guo; Jian Ma; Jin Wang; Jinghong Gao; Mei Tian; Wei Wang; Jia Zhou; Li Jiang; Mengmeng Gu; Sailing Shi; Michael Paull; Guanhua Yang; Wei Yang; Steve Landau; Xingfeng Bao; Xihao Hu; X. Shirley Liu; Tengfei Xiao
• Keywords: Cancer Immunotherapy; Immune checkpoint

Antigen presentation defects in tumors are prevalent mechanisms of adaptive immune evasion and resistance to cancer immunotherapy, whereas how tumors evade innate immunity is less clear. Using CRISPR screens, we discovered that IGSF8 expressed on tumors suppresses NK cell function by interacting with human KIR3DL2 and mouse Klra9 receptors on NK cells. IGSF8 is normally expressed in neuronal tissues and is not required for cell survival in vitro or in vivo. It is overexpressed and associated with low antigen presentation, low immune infiltration, and worse clinical outcomes in many tumors. An antibody that blocks IGSF8-NK receptor interaction enhances NK cell killing of malignant cells in vitro and upregulates antigen presentation, NK cell-mediated cytotoxicity, and T cell signaling in vivo. In syngeneic tumor models, anti-IGSF8 alone, or in combination with anti-PD1, inhibits tumor growth. Our results indicate that IGSF8 is an innate immune checkpoint that could be exploited as a therapeutic target.