Tumoral programmed cell death 1 (PD1) expression in endometrial carcinoma is a prognostic marker for patient outcome

Abstract

ObjectiveImmune checkpoint inhibitors have recently demonstrated benefit in patients with advanced and recurrent endometrial carcinoma. This retrospective study investigated immune checkpoint molecules in endometrial carcinoma as they pertain to the molecular subtypes, clinical outcomes, and predictive value.MethodsTumoral RNA expression of genes controlling the immune checkpoint, programmed cell death 1 (PD1, encoded byPDCD1), its ligand (PDL1, encoded byCD274), and interferon gamma (IFNG) was determined in 239 endometrial carcinoma tissues by quantitative polymerase chain reaction (qPCR) and compared with endometrial tissue from 25 controls. A total of 81 endometrial carcinoma tissues were analyzed using the ProMiSe molecular classification, and patient trajectories were analyzed for the entire cohort. Findings were validated in an independent cohort from The Cancer Genome Atlas (TCGA; n=548).ResultsPD1,PDL1,andIFNGexpression was significantly higher in endometrial carcinoma when compared with non-malignant control tissue with a mean expression of 0.12, 0.05, and 0.05 in control tissue and 0.44, 0.31, and 0.35 in endometrial carcinoma, respectively.POLE-mutated and mismatch repair-deficient (MMRd) (immunologically hot) tumors showed the highest expression ofPD1andIFNG. Increased expression ofPD1,PDL1,andIFNGwas associated with improved recurrence-free (HR 0.32, p<0.001; HR 0.30, p<0.001; HR 0.47, p=0.012, respectively), disease-specific (HR 0.38, p<0.001; HR 0.29, p<0.001; HR 0.45, p=0.017, respectively), and overall survival (HR 0.56, p=0.003; HR 0.38, p<0.001; HR 0.58, p=0.006, respectively). Cox regression confirmed the prognostic significance ofPD1for recurrence-free survival (HR 0.39, p=0.009) andPDL1for overall survival (HR 0.55, p=0.037). The prognostic value of tumoralPD1on recurrence-free survival, disease-specific survival, and overall survival was confirmed in the TCGA cohort.ConclusionsTumoral gene expression controlling the PD1 immune checkpoint, particularly expressed in “hot tumors”, predicted recurrence-free, disease-specific, and overall survival in patients with endometrial carcinoma in two independent cohorts. Evaluation of these genes could be used to stratify patients who qualify for immune checkpoint inhibitors, which warrants prospective clinical trials.