缺陷 (d) DNA 错配修复 (MMR) 是一种生物标志物，可预测实体瘤对 PD-1 阻断免疫疗法产生更好的反应。 dMMR 可由 MMR 基因突变或蛋白质失活引起，可分别通过测序和免疫组织化学检测。为了研究 d​​MMR 在弥漫性大 B 细胞淋巴瘤 (DLBCL) 中的作用，通过靶向下一代测序和免疫组织化学对一大批接受治疗的 DLBCL 患者进行了 MMR 基因突变以及 MSH6、MSH2、MLH1 和 PMS2 蛋白的表达评估与标准化学免疫疗法进行比较，并与通过荧光多重免疫组织化学和基因表达谱定量的肿瘤免疫微环境特征相关。结果显示，遗传性 dMMR 在 DLBCL 中并不常见，并且与癌症基因突变增加和有利的免疫微环境显着相关，但与预后影响无关。表型 dMMR 也很少见，并且 MMR 蛋白通常在 DLBCL 中表达。然而，肿瘤内异质性存在，具有表型 dMMR 的 DLBCL 细胞增加与 T 细胞和 PD-1 T 细胞显着增加、T 细胞和 PAX5 细胞之间平均最近邻距离较高、免疫基因特征上调、LE4 和 LE7 生态型及其潜在相关。 Ecotyper 定义的细胞状态，表明增加的 T 细胞可能仅针对具有 dMMR 的肿瘤细胞亚群。仅在 MYC-DLBCL 患者中，高 MSH6/PMS2 表达显示出显着的不良预后影响。这项研究显示了遗传/表型 dMMR 对 DLBCL 的免疫学和预后影响，并提出了一个问题：DLBCL 浸润的 PD-1 T 细胞是否仅靶向肿瘤亚克隆，这与 PD-1 阻断免疫疗法在 DLBCL 中的疗效相关。© 2024作者。经泰勒许可出版

Deficient (d) DNA mismatch repair (MMR) is a biomarker predictive of better response to PD-1 blockade immunotherapy in solid tumors. dMMR can be caused by mutations in MMR genes or by protein inactivation, which can be detected by sequencing and immunohistochemistry, respectively. To investigate the role of dMMR in diffuse large B-cell lymphoma (DLBCL), MMR gene mutations and expression of MSH6, MSH2, MLH1, and PMS2 proteins were evaluated by targeted next-generation sequencing and immunohistochemistry in a large cohort of DLBCL patients treated with standard chemoimmunotherapy, and correlated with the tumor immune microenvironment characteristics quantified by fluorescent multiplex immunohistochemistry and gene-expression profiling. The results showed that genetic dMMR was infrequent in DLBCL and was significantly associated with increased cancer gene mutations and favorable immune microenvironment, but not prognostic impact. Phenotypic dMMR was also infrequent, and MMR proteins were commonly expressed in DLBCL. However, intratumor heterogeneity existed, and increased DLBCL cells with phenotypic dMMR correlated with significantly increased T cells and PD-1+ T cells, higher average nearest neighbor distance between T cells and PAX5+ cells, upregulated immune gene signatures, LE4 and LE7 ecotypes and their underlying Ecotyper-defined cell states, suggesting the possibility that increased T cells targeted only tumor cell subsets with dMMR. Only in patients with MYC¯ DLBCL, high MSH6/PMS2 expression showed significant adverse prognostic effects. This study shows the immunologic and prognostic effects of genetic/phenotypic dMMR in DLBCL, and raises a question on whether DLBCL-infiltrating PD-1+ T cells target only tumor subclones, relevant for the efficacy of PD-1 blockade immunotherapy in DLBCL.© 2024 The Author(s). Published with license by Taylor & Francis Group, LLC.