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.

1 型传统树突状细胞 (cDC1) 交叉呈递来自死亡肿瘤细胞的抗原被认为是抗癌 CD8 ⁺ T 细胞启动的基础。 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。在这里，我们发现分泌性凝溶胶蛋白 (sGSN)（一种细胞外蛋白）可减少 DNGR-1 与 F-肌动蛋白的结合以及 cDC1 交叉呈递死细胞相关抗原。 sGsn缺陷的小鼠表现出对可移植肿瘤（尤其是表达与肌动蛋白细胞骨架相关的新抗原的肿瘤）的 DNGR-1 依赖性抵抗力增强，并且对癌症免疫治疗表现出更高的反应性。在人类癌症中，肿瘤内sGSN转录物水平较低，以及与肌动蛋白细胞骨架相关的蛋白质中存在突变，与抗癌免疫特征和增加患者生存率相关。我们的结果揭示了癌症抗原交叉呈递的天然屏障，可抑制抗肿瘤 CD8 ⁺ T 细胞反应。