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Abstract：
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.
摘要：
缺陷(d)DNA错配修复(MMR)是预测实体瘤中对PD-1阻断免疫疗法的更好响应的生物标志物。dMMR可由MMR基因突变或蛋白质失活引起，可以通过测序和免疫组织化学检测，分别。探讨dMMR在弥漫大B细胞淋巴瘤(DLBCL)中的作用,MMR基因突变和MSH6，MSH2，MLH1和PMS2蛋白的表达通过靶向下一代测序和免疫组织化学在接受标准化学免疫疗法治疗的大量DLBCL患者中进行评估。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。结果表明，遗传dMMR在DLBCL中很少发生，并且与癌症基因突变增加和良好的免疫微环境显着相关，但不影响预后。表型dMMR也很少见，MMR蛋白在DLBCL中普遍表达。然而,瘤内异质性存在，并且具有表型dMMR的DLBCL细胞增加与T细胞和PD-1T细胞显着增加相关，T细胞和PAX5+细胞之间的平均最近邻距离更高，上调的免疫基因签名，LE4和LE7生态型及其潜在的Ecotyper定义的细胞状态，提示增加的T细胞仅靶向dMMR的肿瘤细胞亚群的可能性。仅在MYCDLBCL患者中，MSH6/PMS2高表达对预后有显著影响.这项研究显示了遗传/表型dMMR在DLBCL中的免疫学和预后作用，并提出了一个问题，即DLBCL浸润性PD-1+T细胞是否仅靶向肿瘤亚克隆，与PD-1阻断免疫疗法在DLBCL中的疗效相关。
