PD-L1 Expression in Endometrial Carcinoma Cells and Intratumoral Immune Cells: Differences Across Histologic and TCGA-based Molecular Subgroups.

Programmed death-ligand 1 (PD-L1) is a biomarker that may predict the response to anti-programmed death 1/PD-L1 immunotherapy. We evaluated the expression of PD-L1 in carcinoma cells (Ca) and immune cells (ICs) across histopathologic and The Cancer Genome Atlas (TCGA) molecular subgroups of endometrial carcinoma (EC). Our study included 842 patients with EC. Direct sequencing of polymerase epsilon (POLE) exonuclease domain hot spots and conventional immunohistochemistry (MLH1, PMS2, MSH2, MSH6, p53) were conducted to identify TCGA classification-based molecular subgroups of EC: POLE-mutated, mismatch repair deficient, no specific molecular profile, and p53 aberrant. Multiplex immunohistochemistry was performed to evaluate PD-L1 expression in Ca and tumor-infiltrating ICs. PD-L1 expression in Ca and in ICs was detected in 8.6% and 27.7% of the cases, respectively. A combined positive score (CPS) was ≥1% in 19.4% of the samples. PD-L1 positivity in Ca and ICs, and CPS correlated with tumor T-cell density (P<0.001). POLE-mutated and mismatch repair-deficient tumors were more likely to present PD-L1-expressing ICs, CPS positivity, and abundant tumor-infiltrating lymphocytes compared with other TCGA subgroups (P<0.001). No differences existed in Ca-PD-L1 expression (P=0.366). Within various histotypes, non-endometrioid carcinomas displayed the highest Ca-PD-L1, ICs, and CPS (P<0.03). Advanced cancers showed more frequent Ca-PD-L1 positivity (P=0.016), and CPS (P=0.029) and IC≥1% (P=0.037) positivity compared with early disease. In conclusion, PD-L1 expression profiles differ between molecular subclasses, histologic subtypes, and disease stage of EC. Prospective studies are needed to explore the predictive value of various PD-L1 scoring systems within the subgroups of EC. CPS presents methodological advantages over cell type-specific scoring systems.