IGSF8 is an innate immune checkpoint and cancer immunotherapy target.

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. [Display omitted] • IGSF8 is highly expressed on malignant cells with antigen presentation defects • IGSF8 interacts with NK receptors to suppress NK cell cytotoxicity • Anti-IGSF8 antibody increases NK cell killing of malignant cells in vitro • Anti-IGSF8 alone or in combination with anti-PD1 inhibits tumor growth in vivo IGSF8, aberrantly expressed on malignant cells, functions as an innate immune checkpoint that inhibits cytotoxicity of natural killer cells. A monoclonal antibody targeting IGSF8 alone, or in combination with immune checkpoint blockade, shows therapeutic potential in preclinical models. [ABSTRACT FROM AUTHOR]

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