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IGSF8 is an innate immune checkpoint and cancer immunotherapy target
Cell ( IF 45.5 ) Pub Date : 2024-04-23 , DOI: 10.1016/j.cell.2024.03.039
Yulong Li 1 , Xiangyang Wu 1 , Caibin Sheng 2 , Hailing Liu 1 , Huizhu Liu 1 , Yixuan Tang 1 , Chao Liu 1 , Qingyang Ding 1 , Bin Xie 1 , Xi Xiao 1 , Rongbin Zheng 1 , Quan Yu 1 , Zengdan Guo 1 , Jian Ma 1 , Jin Wang 1 , Jinghong Gao 1 , Mei Tian 1 , Wei Wang 1 , Jia Zhou 1 , Li Jiang 1 , Mengmeng Gu 1 , Sailing Shi 1 , Michael Paull 2 , Guanhua Yang 1 , Wei Yang 2 , Steve Landau 2 , Xingfeng Bao 2 , Xihao Hu 2 , X Shirley Liu 2 , Tengfei Xiao 1
Cell ( IF 45.5 ) Pub Date : 2024-04-23 , DOI: 10.1016/j.cell.2024.03.039
Yulong Li 1 , Xiangyang Wu 1 , Caibin Sheng 2 , Hailing Liu 1 , Huizhu Liu 1 , Yixuan Tang 1 , Chao Liu 1 , Qingyang Ding 1 , Bin Xie 1 , Xi Xiao 1 , Rongbin Zheng 1 , Quan Yu 1 , Zengdan Guo 1 , Jian Ma 1 , Jin Wang 1 , Jinghong Gao 1 , Mei Tian 1 , Wei Wang 1 , Jia Zhou 1 , Li Jiang 1 , Mengmeng Gu 1 , Sailing Shi 1 , Michael Paull 2 , Guanhua Yang 1 , Wei Yang 2 , Steve Landau 2 , Xingfeng Bao 2 , Xihao Hu 2 , X Shirley Liu 2 , Tengfei Xiao 1
Affiliation
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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 or . 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 and upregulates antigen presentation, NK cell-mediated cytotoxicity, and T cell signaling . 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.
中文翻译：
IGSF8 是先天免疫检查点和癌症免疫治疗靶点
肿瘤中的抗原呈递缺陷是适应性免疫逃避和对癌症免疫治疗产生抵抗的普遍机制，而肿瘤如何逃避先天免疫尚不清楚。通过 CRISPR 筛选，我们发现肿瘤上表达的 IGSF8 通过与 NK 细胞上的人类 KIR3DL2 和小鼠 Klra9 受体相互作用来抑制 NK 细胞功能。 IGSF8 通常在神经元组织中表达，并且不是细胞存活所必需的。它在许多肿瘤中过度表达，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 细胞信号传导。在同基因肿瘤模型中，单独的抗 IGSF8 或与抗 PD1 组合可抑制肿瘤生长。我们的结果表明 IGSF8 是一种先天免疫检查点，可用作治疗靶点。
更新日期：2024-04-23
中文翻译：
IGSF8 是先天免疫检查点和癌症免疫治疗靶点
肿瘤中的抗原呈递缺陷是适应性免疫逃避和对癌症免疫治疗产生抵抗的普遍机制，而肿瘤如何逃避先天免疫尚不清楚。通过 CRISPR 筛选，我们发现肿瘤上表达的 IGSF8 通过与 NK 细胞上的人类 KIR3DL2 和小鼠 Klra9 受体相互作用来抑制 NK 细胞功能。 IGSF8 通常在神经元组织中表达，并且不是细胞存活所必需的。它在许多肿瘤中过度表达，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 细胞信号传导。在同基因肿瘤模型中，单独的抗 IGSF8 或与抗 PD1 组合可抑制肿瘤生长。我们的结果表明 IGSF8 是一种先天免疫检查点，可用作治疗靶点。
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