文章：

临床与分子差异提示高肿瘤突变负荷的微卫星稳定实体瘤对免疫检查点抑制剂的反应存在差异

Clinical and Molecular Differences Suggest Different Responses to Immune Checkpoint Inhibitors in Microsatellite-Stable Solid Tumors with High Tumor Mutational Burden

原文发布日期：16 August 2025

DOI: 10.3390/cancers17162673

类型: Article

开放获取: 是

英文摘要：

Background/Objectives: We aim to identify predictors of response to ICIs in patients with advanced solid tumors that exhibiting a TMB ≥ 10 mut/Mb.Methods: Patients treated with ICIs alone at Northwestern University between 1 January 2015 and 31 December 2020 were identified. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan–Meier method, and groups were compared using the log-rank test. Wilcoxon rank sum tests, chi-squared tests, and Fisher’s exact tests were used for univariable analyses evaluating the impact of clinical and genetic variables on response, with significance defined asp< 0.05.Results: A total of 117 patients were classified as ICI-sensitive (n = 88) or non-ICI-sensitive (n = 29). Among evaluable patients (n = 105), the overall response rate was 34% with 14% achieving a complete response. Median PFS and OS were 8.05 months and 26.8 months, respectively. Higher PFS rates were significantly linked to the ICI-sensitive tumor group (p= 0.009), absence of liver metastasis (p= 0.015), and no prior systemic treatment (p= 0.001) in both cohorts. In non-ICI-sensitive patients, a TMB of ≥15 mut/Mb correlated with improved outcomes (p= 0.012). Mutations in theMYCpathway (p= 0.03) and theMLL2gene (p= 0.014) were associated with poorer responses, while mutations in theTERTgene were linked to better responses (p= 0.031).Conclusions: Patients without liver metastasis, mutations inTERT, and TMB ≥ 15 mut/Mb are associated with superior response, while mutations in theMYCpathway andMLL2are associated with worse responses.

摘要翻译： 

**背景/目的：** 本研究旨在识别肿瘤突变负荷（TMB）≥ 10 突变/兆碱基的晚期实体瘤患者对免疫检查点抑制剂治疗反应的预测因素。 **方法：** 我们筛选了2015年1月1日至2020年12月31日期间在西北大学单独接受ICIs治疗的患者。采用Kaplan-Meier法计算无进展生存期和总生存期，并使用对数秩检验进行组间比较。采用Wilcoxon秩和检验、卡方检验和Fisher精确检验进行单变量分析，评估临床和遗传变量对治疗反应的影响，显著性定义为p < 0.05。 **结果：** 共有117名患者被归类为ICI敏感型（n = 88）或非ICI敏感型（n = 29）。在可评估患者中（n = 105），总体缓解率为34%，其中14%达到完全缓解。中位PFS和OS分别为8.05个月和26.8个月。在两个队列中，较高的PFS率均与ICI敏感型肿瘤组（p = 0.009）、无肝转移（p = 0.015）以及既往未接受过全身治疗（p = 0.001）显著相关。在非ICI敏感型患者中，TMB ≥ 15 突变/Mb与改善的预后相关（p = 0.012）。MYC通路（p = 0.03）和MLL2基因（p = 0.014）的突变与较差的治疗反应相关，而TERT基因突变则与较好的治疗反应相关（p = 0.031）。 **结论：** 无肝转移、存在TERT基因突变以及TMB ≥ 15 突变/Mb的患者与更优的治疗反应相关，而MYC通路和MLL2基因的突变则与较差的治疗反应相关。

原文链接：

Clinical and Molecular Differences Suggest Different Responses to Immune Checkpoint Inhibitors in Microsatellite-Stable Solid Tumors with High Tumor Mutational Burden