PD-L1 expression and immune infiltration across molecular subtypes of endometrial cancer: An integrative-analysis of molecular classification and immune subtypes.

Abstract

The immune subtypes of the tumor microenvironment in endometrial cancer (EC), associated with different molecular classifications, warrant further investigation to guide EC immunotherapy strategies. This study focused on programmed death-ligand 1 (PD-L1) expression (Clone SP263) and immune cell (IC) markers (CD3, CD8, CD68, CD20, CD21) in 110 EC cases. In this cohort, the molecular subtype distribution was: POLE mutation (POLEmut) 7.3% (8/110), mismatch repair-deficient (MMRd) 21.8% (24/110), p53 abnormal (p53abn) 14.5% (16/110), and non-specific molecular profile (NSMP) 56.4% (62/110). NSMP subtypes exhibited the lowest PD-L1+ cell densities and scores. POLEmut and MMRd subtypes showed higher IC densities, while p53abn and NSMP subtypes had lower IC densities and fewer tertiary lymphoid structures (TLS). Integrative analysis of immune subtypes with PD-L1 and CD8⁺ tumor infiltrating lymphocytes (TILs) revealed 62.5% of POLEmut and 45.8% of MMRd cases as TIME type Ⅰ (PD-L1⁺ & CD8^high). Conversely, p53abn and NSMP cases were more heterogeneous, with 37.5% of p53abn cases in TIME type Ⅲ (PD-L1⁺ & CD8^low) and 41.9% of NSMP cases in TIME type Ⅱ (PD-L1^- & CD8^low). Higher CD8⁺ T cell density was a prognostic marker for disease-free survival in EC, including within NSMP (p < 0.05). In summary, the four WHO molecular subtypes of EC exhibit distinct TIME subtypes, complementing molecular classification and providing insights for optimizing EC immunotherapy strategies.