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The Role of Plasmacytoid Dendritic Cells in the Immune Contexture of TP53-Mutated High-Grade Serous Ovarian Cancer
by
, , , , , , , and
Katharina Steger
1,
Heidelinde Fiegl
1,
Katja Rungger
2,
Katharina Leitner
1,
Irina Tsibulak
1,
Barin Feroz
1,
Christoph Ebner
1,
Christian Marth
1,
Hubert Hackl
2,*,†
and
Alain Gustave Zeimet
1,*,† 1
Department of Obstetrics and Gynecology, Medical University of Innsbruck, 6020 Innsbruck, Austria
2
Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, 6020 Innsbruck, Austria
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Cancers 2025, 17(23), 3877; https://doi.org/10.3390/cancers17233877 (registering DOI)
Submission received: 26 October 2025
/
Revised: 23 November 2025
/
Accepted: 2 December 2025
/
Published: 3 December 2025
(This article belongs to the Special Issue Cancer Immunotherapy as Part of Precision Clinical Medicine)
Simple Summary
High-grade serous ovarian cancer (HGSOC), triple-negative breast cancer, and a subset of endometrial cancers frequently share mutations in the TP53 gene, one of the most frequently mutated tumor suppressor genes across human cancers. Despite this common genetic background, these cancers often do not respond well to modern immunotherapies. Dendritic cells, which act as messengers between the innate and adaptive immune systems, may play a crucial role in shaping the immune environment of such tumors. In this study, we analyzed tumor samples from 603 patients to explore the distribution of different dendritic cell subsets and their relationship to patient outcomes. We found that a specific subset, plasmacytoid dendritic cells, appears to exert a clinically relevant tumor-promoting role in TP53-mutated HGSOC, potentially contributing to immune evasion. Selective targeting of dendritic cell subsets could offer novel therapeutic strategies in TP53-mutated malignancies with low tumor mutational burden such as HGSOC.
Abstract
Background/Objectives: This study aimed to characterize dendritic cell (DC) heterogeneity, immune associations, and prognostic relevance across three TP53-mutated tumor entities—high-grade serous ovarian cancer (HGSOC), triple-negative breast cancer, and endometrial cancer—focusing on plasmacytoid DCs (pDCs) in HGSOC. Methods: RNA-sequencing and clinical data of 603 patients from The Cancer Genome Atlas were analyzed. DC subset abundance was assessed for cDC progenitor, conventional DC type 1 (cDC1), conventional DC type 2 (cDC2), plasmacytoid DC (pDC), and mature DC by marker gene signatures. Differences in DC scores across tumors were analyzed using Kruskal–Wallis. Survival analyses were performed using Kaplan–Meier and Cox regression. Spearman’s correlation was used to determine associations between parameters. Results: HGSOC showed the lowest pDC abundance, yet high pDC scores were independently associated with shorter PFS (HR = 1.55, 95% CI: 1.05–2.27; p = 0.027), representing the only DC-subset-related prognostic signal observed across tumor types. pDCs correlated positively with neutrophils and negatively with monocytes, and pDCs, cDC2s, and cDC progenitors correlated inversely with TMB. No consistent link was found between pDC and TP53 mutation classes. However, tumors harboring specific TP53 mutations within established hotspot regions exhibited significantly lower pDC levels (p = 0.015). Conclusions: Our findings reveal distinct DC infiltration patterns and highlight the immunological vulnerability of TP53-mutated HGSOC. pDCs appear to exert a tumor-promoting, immune-evasive role, suggesting that DC function depends on their programming and tumor context. Selective targeting of DC subsets may offer novel therapeutic opportunities in TP53-mutated, low-TMB cancers.
