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. 2025 Mar 26:219:115320.
doi: 10.1016/j.ejca.2025.115320. Epub 2025 Feb 20.

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

Katharina Steger  1 , Heidelinde Fiegl  1 , Barin Feroz  1 , Katharina Leitner  1 , Christian Marth  1 , Hubert Hackl  2 , Alain G Zeimet  3
Affiliations
Free article

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

Katharina Steger et al. Eur J Cancer. .
Free article

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.

Keywords: Biomarker; Cancer genomics; Immuno-oncology; Immunotherapy; TP53 mutation.

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Conflict of interest statement

Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: KS reports travel expenses from Roche, Daiichi Sankyo, GSK, and Pharma Mar. HH reports research funding from CatalYm and Secarna. KL reports support for attending meeting and travel from Gilead, GSK, Eisai, and Roche. HF reports no conflicts of interest. BF reports travel expenses from Roche, Pfizer, and Lilly. CM reports consulting fees from Roche, Novartis, Amgen, MSD, PharmaMar, Astra Zeneca, GSK, and Seagen; honoraria from Roche, Novartis, Amgen, MSD, PharmaMar, Astra Zeneca, GSK, and Seagen; travel expenses from Roche and Astra Zeneca; participation on advisory boards from Roche, Novartis, Amgen, MSD, Astra Zeneca, Pfizer, PharmaMar, GSK, and Seagen. AGZ reports consulting fees from Amgen, Astra Zeneca, GSK, MSD, Novartis, PharmaMar, Roche-Diagnostics, and Seagen; honoraria from Amgen, Astra Zeneca, GSK, MSD, Novartis, PharmaMar, Roche, and Seagen; travel expenses from Astra Zeneca, Gilead, and Roche; participation on advisory boards from Amgen, Astra Zeneca, GSK, MSD, Novartis, Pfizer, PharmaMar, Roche, and Seagen. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article.

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