Spatiotemporal Immune Landscape and Long-term Immune Memory in POLE-Mutant Endometrial Cancer at the Single-Cell Level

Abstract Polymerase epsilon–mutant (POLE-mut) endometrial cancers are characterized by a near 100% disease-specific survival rate, even when treated with surgery alone. This 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 analysis of immune infiltration in POLE-mut endometrial cancers has predominantly been confined to IHC studies. In this study, we used single-cell RNA and T-cell receptor sequencing to characterize the immune landscape of POLE-mut endometrial cancers. Moreover, we analyzed patient blood samples taken 2 to 8 years after curative treatment to assess the 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 NK cells, as well as tumor-reactive exhausted and effector T cells, all contributing to a highly inflammatory antitumor response. 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 endometrial cancer survivors. Our study highlights the distinctive immunogenicity of POLE-mut endometrial cancer and identifies key features associated with persistent antitumor immunity that may contribute to prolonged, relapse-free survival.