Endometrial carcinoma and immune escape: prognostic relevance of HLA class I loss in NSMP subtype

Aims: This study aims to define and characterize human leukocyte antigen class I (HLA-I) expression in a consecutive series of molecularly classified endometrial carcinomas (ECs), and to evaluate its association with clinicopathologic features, spatial cancer–immune phenotypes and patient prognosis, with a focus on the NSMP (no specific molecular profile) subtype. Methods and results: HLA-I expression was assessed by immunohistochemistry on whole tissue sections from 208 ECs, classified into POLE-mutated, MMR-deficient (MMRd), p53-abnormal (p53abn) and NSMP subtypes. Loss of HLA-I was identified in 31% of cases and was associated with adverse features including high-grade, aggressive histotypes, deep myometrial invasion, substantial lymphovascular space invasion (LVSI), extensive tumour necrosis and an ‘excluded’ immune phenotype. While HLA-I loss showed no significant prognostic impact in POLE, MMRd or p53abn tumours, it significantly correlated with worse disease-free survival in NSMP tumours (P < 0.001). Multivariate analysis confirmed HLA-I loss as an independent prognostic factor in early-stage NSMP ECs, in addition to substantial LVSI, presence of lymph node metastases and spatial cancer–immune phenotypes. Integration of HLA-I status improved the performance of predictive models over time. Conclusions: HLA-I loss defines a biologically aggressive subgroup within NSMP ECs and is associated with adverse clinicopathologic and immune features. Assessment of HLA-I expression could refine risk stratification in NSMP ECs, a group traditionally lacking robust prognostic markers and may help identify patients who could benefit from intensified clinical surveillance and future immunomodulatory treatment strategies.