英国弗朗西斯·克里克研究所Caetano Reis e Sousa团队发现，分泌的凝溶胶蛋白抑制DNGR-1依赖性交叉呈递和癌症免疫。相关论文于2021年6月2日在线发表在《细胞》杂志上。

研究人员表示，1型常规树突状细胞 (cDC1) 交叉呈递来自死亡肿瘤细胞的抗原，并被认为是引发抗癌CD8⁺ T细胞的基础。cDC1表达高水平的DNGR-1（又名CLEC9A），这是一种与死细胞碎片暴露的F-肌动蛋白结合并促进相关抗原交叉呈递的受体。

研究人员发现，分泌的凝溶胶蛋白 (sGSN，一种细胞外蛋白）减少了DNGR-1与F-肌动蛋白的结合以及cDC1对死细胞相关抗原的交叉呈递。缺乏sGsn的小鼠对可移植肿瘤的DNGR-1依赖性耐药性增加，尤其是那些表达与肌动蛋白细胞骨架相关的新抗原的肿瘤，并对癌症免疫疗法表现出更高的反应性。在人类癌症中，较低水平的肿瘤内sGSN转录本以及与肌动蛋白细胞骨架相关的蛋白质中的突变与抗肿瘤免疫的特征和患者存活率的增加有关。这些结果揭示了癌症抗原交叉呈递的天然屏障，并可抑制抗肿瘤CD8⁺ T细胞反应。

附：英文原文

Title: Secreted gelsolin inhibits DNGR-1-dependent cross-presentation and cancer immunity

Author: Evangelos Giampazolias, Oliver Schulz, Kok Haw Jonathan Lim, Neil C. Rogers, Probir Chakravarty, Naren Srinivasan, Oliver Gordon, Ana Cardoso, Michael D. Buck, Enzo Z. Poirier, Johnathan Canton, Santiago Zelenay, Stefano Sammicheli, Natalia Moncaut, Sunita Varsani-Brown, Ian Rosewell, Caetano Reis e Sousa

Issue&Volume: 2021-06-02

Abstract: Cross-presentation of antigens from dead tumor cells by type 1 conventional dendritic cells (cDC1s) is thought to underlie priming of anti-cancer CD8+ T cells. cDC1 express high levels of DNGR-1 (a.k.a. CLEC9A), a receptor that binds to F-actin exposed by dead cell debris and promotes cross-presentation of associated antigens. Here, we show that secreted gelsolin (sGSN), an extracellular protein, decreases DNGR-1 binding to F-actin and cross-presentation of dead cell-associated antigens by cDC1s. Mice deficient in sGsn display increased DNGR-1-dependent resistance to transplantable tumors, especially ones expressing neoantigens associated with the actin cytoskeleton, and exhibit greater responsiveness to cancer immunotherapy. In human cancers, lower levels of intratumoral sGSN transcripts, as well as presence of mutations in proteins associated with the actin cytoskeleton, are associated with signatures of anti-cancer immunity and increased patient survival. Our results reveal a natural barrier to cross-presentation of cancer antigens that dampens anti-tumor CD8+ T cell responses.

DOI: 10.1016/j.cell.2021.05.021

Source: https://www.cell.com/cell/fulltext/S0092-8674(21)00651-6