在癌症实验模型中通过定制化学诱变诱导错配修复缺陷基因型，这一成果由美国纪念斯隆-凯特琳癌症中心Luis A. Diaz研究小组经过不懈努力而取得。2025年6月12日，国际知名学术期刊《癌细胞》发表了这一成果。

课题组人员试图复制这种表型主题诱变剂，以在免疫抗性细胞中设计MMRd基因型。替莫唑胺（TMZ）和顺铂联合使用可导致小鼠细胞系中因Msh2的表观遗传缺失而富集的高突变负荷的快速积累。预处理细胞对PD-1阻断反应敏感。在不影响健康组织的情况下，用TMZ、顺铂和抗pd -1免疫耐药肿瘤细胞进行全身治疗，可提高生存率、瘤内T细胞浸润和下调Msh2表达。在18例难治性错配修复熟练的结直肠癌患者的临床试验中，没有看到反应，但在无细胞DNA中出现了MMRd特征。这些发现表明，通过化学诱变重述MMRd基因型可以产生免疫原性表型。

据介绍，错配修复缺陷（MMRd）肿瘤含有丰富的插入缺失（indels）体细胞突变，对免疫治疗具有高度敏感性。

附：英文原文

Title: Induction of a mismatch repair deficient genotype by tailored chemical mutagenesis in experimental models of cancer

Author: Benoit Rousseau, Mitesh Patel, Oliver Artz, Georgios Vlachos, Shrey Patel, Omar Hayatt, Guillem Argilés, Michael B. Foote, Lingqi Luo, Rachna Shah, Shub Mehta, Karthik Rangavajhula, Caitlin- M. Stewart, Drew Gerber, Rohini Bhattacharya, Dennis Stephens, David Mieles, Violaine Randrian, Somer Abdelfattah, Lin Zhang, Nathalie Membreno-Berganza, Michelle F. Lamendola-Essel, Florence Piastra-Facon, Joana Vidal, Paul Johannet, Steve Lu, James R. White, Steven B. Maron, Afsar Barlas, Caroline M. Weipert, Eric Rosiek, Taotao Zhang, Bing He, Sebastien Monette, Rui Qu, Deborah Fidele, Sydney Bowker, Alec Kahn, Pietro Paolo Vitiello, Giovanni Germano, Alberto Bardelli, Rajarsi Mandal, Xiaoxiao Ma, Tim A. Chan, Sydney Lu, Andrea Cercek, Omar Abdel-Wahab, Elisa de Stanchina, Neil H. Segal, Luis A. Diaz

Issue&Volume: 2025-06-12

Abstract: Mismatch repair deficient (MMRd) tumors harbor thousands of somatic mutations enriched for insertion–deletion (indels) conferring high sensitivity to immunotherapy. We sought to reproduce this phenotype using mutagenic agents to engineer an MMRd genotype in immunoresistant cells. The combination of temozolomide (TMZ) and cisplatin led to a rapid accumulation of a high mutational load enriched for indels in murine cell lines resulting from the epigenetic loss of Msh2. Pretreated cells showed sensitivity to PD-1 blockade. Systemic treatment with TMZ, cisplatin, and anti-PD-1 bearing immunoresistant tumor cells led to increased survival, intratumoral T cell infiltration, and downregulation of Msh2 expression without affecting healthy tissues. In a clinical trial with 18 patients with refractory mismatch repair proficient colorectal cancer, no responses were seen, but MMRd signatures emerged in cell-free DNA. These findings show that recapitulating an MMRd genotype through chemical mutagenesis can generate an immunogenic phenotype.

DOI: 10.1016/j.ccell.2025.05.010

Source: https://www.cell.com/cancer-cell/abstract/S1535-6108(25)00219-3