Colorectal cancers (CRCs) deficient in DNA mismatch repair (dMMR) contain abundant CD8⁺ tumor-infiltrating lymphocytes (TILs) responding to the abundant neoantigens from their unstable genomes. Priming of such tumor-targeted TILs first requires recruitment of CD8⁺ T cells into the tumors, implying that this is an essential prerequisite of successful dMMR anti-tumor immunity. We have discovered that selective recruitment and activation of systemic CD8⁺ T cells into dMMR CRCs strictly depend on overexpression of CCL5 and CXCL10 due to endogenous activation of cGAS/STING and type I IFN signaling by damaged DNA. TIL infiltration into orthotopic dMMR CRCs is neoantigen-independent and followed by induction of a resident memory-like phenotype key to the anti-tumor response. CCL5 and CXCL10 could be up-regulated by common chemotherapies in all CRCs, indicating that facilitating CD8⁺ T cell recruitment underlies their efficacy. Induction of CCL5 and CXCL10 thus represents a tractable therapeutic strategy to induce TIL recruitment into CRCs, where local priming can be maximized even in neoantigen-poor CRCs.

中文翻译：

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错配修复缺陷型结直肠癌的抗肿瘤免疫需要 I 型 IFN 驱动的 CCL5 和 CXCL10

缺乏 DNA 错配修复 (dMMR) 的结直肠癌 (CRC) 含有丰富的 CD8 ⁺肿瘤浸润淋巴细胞 (TIL)，它们对来自其不稳定基因组的大量新抗原作出反应。此类肿瘤靶向 TIL 的启动首先需要将 CD8 ⁺ T 细胞募集到肿瘤中，这意味着这是成功进行 dMMR 抗肿瘤免疫的必要先决条件。我们发现选择性募集和激活系统性 CD8 ⁺由于 cGAS/STING 的内源性激活和受损 DNA 的 I 型 IFN 信号传导，进入 dMMR CRC 的 T 细胞严格依赖于 CCL5 和 CXCL10 的过表达。TIL 浸润到原位 dMMR CRC 中是不依赖于新抗原的，然后诱导一种常驻记忆样表型，这是抗肿瘤反应的关键。CCL5 和 CXCL10 可以通过所有 CRC 中的常见化学疗法上调，这表明促进 CD8 ⁺ T 细胞募集是其功效的基础。因此，CCL5 和 CXCL10 的诱导代表了一种易于处理的治疗策略，可将 TIL 募集到 CRCs 中，即使在缺乏新抗原的 CRCs 中也可以最大化局部启动。