2024年4月23日，來自尋百匯生物肖騰飛團隊在《細胞》發表了標題為”IGSF8 is an innate immune checkpoint and cancer immunotherapy target.“的研究成果。研究顯示IGSF8是一種先天免疫檢查點和腫瘤免疫治療靶點。
研究人員表示，腫瘤抗原呈遞缺陷是適應性免疫逃避和腫瘤免疫治療抵抗的普遍機制，而腫瘤如何逃避先天免疫尚不清楚。
通過CRISPR篩選，研究組發現IGSF8通過與NK細胞中的人KIR3DL2和小鼠Klra9受體相互作用，來抑制腫瘤NK細胞的功能。IGSF8通常在神經組織中表達，在體外或體內都不是細胞存活所必需的。在許多腫瘤中，它過表達并與低抗原呈遞、低免疫浸潤和較差的臨床結果相關。
阻斷IGSF8-NK受體相互作用的抗體在體外增強NK細胞對惡性細胞的殺傷，并在體內上調抗原呈遞、NK細胞介導的細胞毒性和T細胞信號傳導。在同基因腫瘤模型中，單獨抗IGSF8或與抗PD1聯合抑制腫瘤生長。他們的結果表明IGSF8是一種先天免疫檢查點，可以作為治療靶點。
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.
文章來源：
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
