Dedifferentiation in endometrial cancer is associated with HLA ‐I silencing that may be restored by IFN ‐γ

Abstract

Dedifferentiated endometrial carcinoma occurs when a prognostically favorable low‐grade endometrial carcinoma transforms into a highly aggressive undifferentiated carcinoma following genomic inactivation of core SWItch/Sucrose Non‐Fermentable (SWI/SNF) complex protein(s). This typically occurs in a microsatellite‐instable molecular context. This study aims to identify the immune evasion mechanisms associated with dedifferentiation. Whole‐slide immunohistochemistry‐based image analysis was used to compare spatial cancer immunophenotypes and human leukocyte antigen class I (HLA‐I) expression between the differentiated and undifferentiated components of 14 SWI/SNF‐inactivated dedifferentiated endometrial carcinomas. Flow cytometry and in vivo xenograft studies were performed to gain functional insights. Dedifferentiation was associated with changes in spatial cancer immunophenotypes, most frequently from an inflamed immunophenotype in the differentiated component to an excluded immunophenotype in the undifferentiated component, with loss of tumor HLA‐I expression, decreased intraepithelial CD8 ⁺ T‐cell, and increased stromal PD‐L1 ⁺ immune infiltrates. Loss of tumor surface HLA‐I expression was also observed in the undifferentiated carcinoma from two patient‐derived models of dedifferentiated endometrial carcinomas – DDEC1 and DDEC2. By flow cytometry, IFN‐γ treatment restored HLA‐I expression in DDEC2 (3.5‐fold increase, p  < 0.05) but not in DDEC1, which harbored inactivating JAK1 mutations. In the in vivo xenograft model of DDEC2, intratumoral injection of IFN‐γ restored HLA‐I expression in the undifferentiated tumors. These findings implicate the loss of tumor HLA‐I expression as an immune evasion mechanism acquired during dedifferentiation in a subset of dedifferentiated endometrial carcinomas. More importantly, IFN‐γ can restore tumor HLA‐I expression, providing a rationale for combining it with immune checkpoint inhibitors in the treatment of this clinically aggressive cancer type. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.