2024年4月23日，来自寻百汇生物肖腾飞团队在《细胞》发表了标题为”IGSF8 is an innate immune checkpoint and cancer immunotherapy target.“的研究成果。研究显示IGSF8是一种先天免疫检查点和肿瘤免疫治疗靶点。
研究人员表示，肿瘤抗原呈递缺陷是适应性免疫逃避和肿瘤免疫治疗抵抗的普遍机制，而肿瘤如何逃避先天免疫尚不清楚。
通过CRISPR筛选，研究组发现IGSF8通过与NK细胞中的人KIR3DL2和小鼠Klra9受体相互作用，来抑制肿瘤NK细胞的功能。IGSF8通常在神经组织中表达，在体外或体内都不是细胞存活所必需的。在许多肿瘤中，它过表达并与低抗原呈递、低免疫浸润和较差的临床结果相关。
阻断IGSF8-NK受体相互作用的抗体在体外增强NK细胞对恶性细胞的杀伤，并在体内上调抗原呈递、NK细胞介导的细胞毒性和T细胞信号传导。在同基因肿瘤模型中，单独抗IGSF8或与抗PD1联合抑制肿瘤生长。他们的结果表明IGSF8是一种先天免疫检查点，可以作为治疗靶点。
Highlights
- 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
Summary
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.
文章来源：
Yulong Li, Xiangyang Wu, Caibin Sheng et al, IGSF8 is an innate immune checkpoint and cancer immunotherapy target.DOI: 10.1016/j.cell.2024.03.039，Cell：最新IF：66.85
