Shanghai Xunbaihui Biotechnology Co., Ltd., 3rd floor of Building 4, No. 3728, Jinke Road, Pudong New Area, Shanghai, 201203, China.
GV20 Therapeutics LLC, 237 Putnam Avenue, Cambridge, MA 02139, USA.
Cell. 2024 May 23;187(11):2703-2716.e23. doi: 10.1016/j.cell.2024.03.039. Epub 2024 Apr 23.
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.
肿瘤中的抗原呈递缺陷是适应性免疫逃逸和癌症免疫治疗耐药的普遍机制，而肿瘤如何逃避先天免疫尚不清楚。使用 CRISPR 筛选，我们发现肿瘤细胞表面表达的 IGSF8 通过与 NK 细胞上的人 KIR3DL2 和小鼠 Klra9 受体相互作用，抑制 NK 细胞功能。IGSF8 在神经组织中正常表达，在体外或体内均不需要细胞存活。在许多肿瘤中，它过度表达，并与低抗原呈递、低免疫浸润和更差的临床结果相关。阻断 IGSF8-NK 受体相互作用的抗体可增强 NK 细胞对恶性细胞的杀伤作用，并上调抗原呈递、NK 细胞介导的细胞毒性和 T 细胞信号转导。在同种异体肿瘤模型中，单独使用抗 IGSF8 或与抗 PD1 联合使用，可抑制肿瘤生长。我们的研究结果表明，IGSF8 是一种先天免疫检查点，可作为治疗靶点。
