受结直肠癌（CRC）DNA错配修复缺陷（MMRd）影响的患者，通常对免疫检查点抑制疗法做出反应，而具有错配修复有效（MMRp）肿瘤的患者通常不会做出反应。有趣的是，一部分MMRp CRCs包含可变比例的MMRd细胞，但它们的存在如何影响免疫监视尚不清楚。我们询问调节MMR杂合瘤中MMRd分数是否作为内源性癌症疫苗促进免疫监视。为了测试这个猜想，我们使用同系性MMRp（Mlh1+/+）和MMRd（Mlh1-/-）小鼠CRC细胞。混合不同比例的MMRp/MMRd细胞注入免疫能力良好的小鼠，当至少50%的细胞为MMRd时观察到肿瘤排斥。为了富集MMRd分数，MMRp/MMRd肿瘤接受6-硫鸟嘌呤治疗，导致肿瘤排斥。这些结果表明，DNA错配修复机制的遗传学和药理学调节增强了MMR杂合瘤的免疫原性。版权所有©2022作者。由Elsevier Inc.出版。保留所有权利。

Patients affected by colorectal cancer (CRC) with DNA mismatch repair deficiency (MMRd), often respond to immune checkpoint blockade therapies, while those with mismatch repair-proficient (MMRp) tumors generally do not. Interestingly, a subset of MMRp CRCs contains variable fractions of MMRd cells, but it is unknown how their presence impacts immune surveillance. We asked whether modulation of the MMRd fraction in MMR heterogeneous tumors acts as an endogenous cancer vaccine by promoting immune surveillance. To test this hypothesis, we use isogenic MMRp (Mlh1+/+) and MMRd (Mlh1-/-) mouse CRC cells. MMRp/MMRd cells mixed at different ratios are injected in immunocompetent mice and tumor rejection is observed when at least 50% of cells are MMRd. To enrich the MMRd fraction, MMRp/MMRd tumors are treated with 6-thioguanine, which leads to tumor rejection. These results suggest that genetic and pharmacological modulation of the DNA mismatch repair machinery potentiate the immunogenicity of MMR heterogeneous tumors.Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.