Cancer Immunol Res. 2025 Aug 29. doi: 10.1158/2326-6066.CIR-25-0083. Online ahead of print.
ABSTRACT
Polymerase epsilon mutant (POLE-mut) endometrial cancers (EC) are characterized by a near 100% disease-specific survival rate, even when treated by surgery alone. This spectacular survival, combined with the ultramutated genome and high level of neoantigens in these tumors, indicates a substantial degree of immune control in preventing disease spread and recurrence. Although these features are intriguing, the immune infiltration of POLE-mut EC has predominantly been confined to immunohistochemistry studies. Here, we used state of the art single-cell RNA and TCR sequencing to characterize the immune landscape of POLE-mutant ECs. Moreover, we uniquely analyzed patient blood samples taken two to eight years after curative treatment to assess formation of long-term immune memory in circulation. We identified specialized tumor-infiltrating myeloid subsets at different stages of maturation, an array of lymphocytes ranging from immature to cytotoxic and adaptive natural killer (NK) as well as tumor-reactive exhausted and effector T cells, contributing to a highly inflammatory anti-tumor response. Remarkably, our analysis of blood samples taken years after curative treatment uncovered the presence of tumor-reactive T cell clones that matched the primary tumor. This indicates the formation of systemic long-term memory immune responses in POLE-mut EC survivors. Our study highlights the distinctive immunogenicity of POLE-mut EC and identifies key features associated with persistent anti-tumor immunity that may contribute to prolonged, relapse-free survival.
PMID:40879333 | DOI:10.1158/2326-6066.CIR-25-0083