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Spatiotemporal Immune Landscape and Long-term Immune Memory in POLE-Mutant Endometrial Cancer at the Single-Cell
Koen Brummel1, Marta Requesens1, Nienke van Rooij1
1Department of Obstetrics and Gynecology, University Medical Centre Groningen, Groningen, the Netherlands.
Cancer Immunology Research
|August 29, 2025
Summary
Polymerase epsilon mutant (POLE-mut) endometrial cancers exhibit strong immune control, leading to high survival rates. Long-term immune memory, including tumor-reactive T cells, is present in survivors years after treatment.
Area of Science:
- Oncology
- Immunology
- Genomics
Background:
- Polymerase epsilon mutant (POLE-mut) endometrial cancers (EC) show exceptional survival rates, suggesting significant immune system involvement.
- Previous studies on POLE-mut EC immunity relied mainly on immunohistochemistry, limiting detailed characterization.
- The ultramutated genome and high neoantigen load in POLE-mut EC imply a strong anti-tumor immune response.
Purpose of the Study:
- To comprehensively characterize the immune landscape within POLE-mut EC using advanced single-cell sequencing.
- To investigate the presence and nature of long-term immune memory in the circulation of POLE-mut EC survivors post-treatment.
- To identify immune features contributing to the favorable prognosis and relapse-free survival in POLE-mut EC.
Main Methods:
- Single-cell RNA sequencing and T cell receptor (TCR) sequencing were employed to analyze tumor-infiltrating immune cells.
- Blood samples from patients treated 2-8 years prior were analyzed to assess systemic immune memory.
- Bioinformatic analyses were performed to identify immune cell subsets, their states, and tumor-specific responses.
Main Results:
- Identification of diverse myeloid cell subsets and various lymphocyte populations, including cytotoxic, adaptive NK, exhausted, and effector T cells.
- Detection of a highly inflammatory anti-tumor response within the tumors.
- Discovery of tumor-reactive T cell clones in the blood of long-term survivors, matching the primary tumor, indicating sustained systemic immune memory.
Conclusions:
- POLE-mut EC possesses a distinctive and highly immunogenic profile.
- The presence of specialized immune cells and long-term systemic immune memory contributes to the excellent clinical outcomes and relapse-free survival.
- These findings offer insights into leveraging anti-tumor immunity for improved endometrial cancer treatment strategies.
