Differences in immunogenicity of TP53-mutated cancers with low tumor mutational burden (TMB) A study on TP53mut endometrial-, ovarian- and triple-negative breast cancer

IF 7.6 1区医学 Q1 ONCOLOGY

European Journal of Cancer Pub Date : 2025-02-20 DOI:10.1016/j.ejca.2025.115320

Katharina Steger , Heidelinde Fiegl , Barin Feroz , Katharina Leitner , Christian Marth , Hubert Hackl , Alain G. Zeimet

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引用次数: 0

Abstract

Purpose

To explore why in large phase III randomized clinical trials TP53-mutated (TP53mut) endometrial cancer (EC) was the only tumor showing survival benefit to immune checkpoint inhibitors (ICIs) added to chemotherapy when compared with other low TMB TP53mut cancers, such as high-grade serous ovarian (HGSOC) and triple-negative breast cancer (TNBC).

Experimental Design

From 606 patients with one of the three mentioned cancers, “The Cancer Genome Atlas” data on clinical outcome, TMB and detailed composition of the tumor immune-microenvironment (TIME) (immune infiltrating cells, cytokines, and other immune-modulators) were compared using the Kruskal-Wallis test, followed by Pearson correlation. Prognostic value of studied variables was assessed by Kaplan-Meier and Cox-regression analyses.

Results

TMB was very low in all three TP53mut entities, being lowest in EC (median: 1.27 Mut/Mb; p < 0.001). Interestingly, high TMB was significantly associated with improved clinical outcome in every entity, whereby best discrimination for PFS was found in EC (HR: 0.52). Compared to EC, immune-suppressing regulatory T-cells were higher in HGSOC and TNBC (p < 0.001) and M2-like macrophages higher in HGSOC (p < 0.001). In contrast, immune-activating mDCs were more prominent in EC than in HGSOC (p < 0.001). Differential modulator expression analyses revealed highest discrimination for the immune-inhibiting FOXP3, C1QA and XBP1, which all exhibited lower levels in EC compared with HGSOC and TNBC (p < 0.001).

Conclusion

Characteristics of TIME differ substantially among the assessed entities in terms that EC exhibits fewer immunosuppressive traits, expecting a higher likelihood for responding to ICIs, despite a very low TMB, whereas HGSOC and TNBC exhibit an immune hostile TIME.

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低肿瘤突变负荷（tumor mutational burden， TMB）的tp53突变癌症的免疫原性差异子宫内膜癌、卵巢癌和三阴性乳腺癌的研究

目的探讨为什么在大型III期随机临床试验中，与其他低TMB TP53mut癌症(如高级别浆液性卵巢癌（HGSOC）和三阴性乳腺癌（TNBC）相比，tp53突变（TP53mut）子宫内膜癌（EC）是唯一一个在化疗中添加免疫检查点抑制剂（ICIs）的肿瘤。实验设计：从606例上述三种癌症之一的患者中，使用Kruskal-Wallis检验比较“癌症基因组图谱”中关于临床结局、TMB和肿瘤免疫微环境（TIME）（免疫浸润细胞、细胞因子和其他免疫调节剂）的详细组成的数据，然后使用Pearson相关性。采用Kaplan-Meier和cox -回归分析评估研究变量的预后价值。结果三种TP53mut实体的stmb都很低，其中EC最低(中位数：1.27 Mut/Mb；p & lt; 0.001)。有趣的是，在每个实体中，高TMB与改善的临床结果显着相关，因此在EC中发现PFS的最佳区分（HR: 0.52）。与EC相比，免疫抑制调节性t细胞在HGSOC和TNBC中较高（p <； 0.001），m2样巨噬细胞在HGSOC中较高（p <； 0.001）。相比之下，免疫激活mDCs在EC中比在HGSOC中更突出（p <； 0.001）。差异调节剂表达分析显示，免疫抑制FOXP3、C1QA和XBP1的差异最高，与HGSOC和TNBC相比，它们在EC中的表达水平都较低（p <； 0.001）。尽管TMB非常低，但EC表现出较少的免疫抑制特征，预期对ICIs反应的可能性更高，而HGSOC和TNBC表现出免疫敌对时间，这在被评估实体之间存在很大差异。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

European Journal of Cancer 医学-肿瘤学

CiteScore

11.50

自引率

4.80%

发文量

953

审稿时长

23 days

期刊介绍： The European Journal of Cancer (EJC) serves as a comprehensive platform integrating preclinical, digital, translational, and clinical research across the spectrum of cancer. From epidemiology, carcinogenesis, and biology to groundbreaking innovations in cancer treatment and patient care, the journal covers a wide array of topics. We publish original research, reviews, previews, editorial comments, and correspondence, fostering dialogue and advancement in the fight against cancer. Join us in our mission to drive progress and improve outcomes in cancer research and patient care.