DNA不匹配修复缺陷（MMRd）与高肿瘤突变负荷（TMB）和免疫检查点阻断（ICB）疗法的敏感性相关。然而，大多数MMRd肿瘤对ICB的持久反应有限，并且关于免疫监视和这些肿瘤中TMB的关键问题仍然存在。在本研究中，我们开发了MMRd肺部和结肠癌的原位小鼠模型。出人意料的是，这些模型没有显示出增加的T细胞浸润或ICB反应，我们发现这是突变的大量肿瘤内异质性的结果。此外，我们发现，免疫监视塑造了克隆体结构，但并未影响新抗原的总负荷，并且对亚克隆的新抗原的T细胞反应被削弱。最后，我们证明克隆性新抗原负荷预示着MMRd胃癌和结直肠癌的临床试验中的ICB反应。这些结果为理解高TMB癌症的免疫逃逸提供了重要的背景，并对旨在增加TMB的治疗方案产生重大影响。©2023. 作者

DNA mismatch repair deficiency (MMRd) is associated with a high tumor mutational burden (TMB) and sensitivity to immune checkpoint blockade (ICB) therapy. Nevertheless, most MMRd tumors do not durably respond to ICB and critical questions remain about immunosurveillance and TMB in these tumors. In the present study, we developed autochthonous mouse models of MMRd lung and colon cancer. Surprisingly, these models did not display increased T cell infiltration or ICB response, which we showed to be the result of substantial intratumor heterogeneity of mutations. Furthermore, we found that immunosurveillance shapes the clonal architecture but not the overall burden of neoantigens, and T cell responses against subclonal neoantigens are blunted. Finally, we showed that clonal, but not subclonal, neoantigen burden predicts ICB response in clinical trials of MMRd gastric and colorectal cancer. These results provide important context for understanding immune evasion in cancers with a high TMB and have major implications for therapies aimed at increasing TMB.© 2023. The Author(s).