Understanding the Impact of Spatial Immunophenotypes on the Survival of Endometrial Cancer Patients through the ProMisE Classification

Objectives We focused on how the immunophenotypes based on the distribution of CD8-positive tumor-infiltrating lymphocytes (TILs) relate to the endometrial cancer (EC) molecular subtypes and patients’ prognosis. Patients and Methods: Two cohorts of EC patients (total n = 145) were analyzed and categorized using the Molecular Risk Classifier for Endometrial cancer (ProMisE): POLEmut ( POLE mutation), MMRd (mismatch repair deficiency), NSMP (no specific molecular profile), and p53abn (p53 abnormality). CD8-positive TILs, within the central tumor and the invasive margin, were examined by using immunohistochemical staining and advanced image-analysis software. It was investigated whether these immunophenotypes correlate with the patients' survival and molecular subtypes. RNA sequencing (RNA-seq) was used to explore tumor-derived factors influencing these immunophenotypes. Results Three distinct immunophenotypes (inflamed, excluded, and desert) based on the CD8-positive TIL patterns were identified in EC patients. The prognosis was markedly poorer in the patients with the non-inflamed (desert or excluded) phenotype than in those with the inflamed phenotype. Notably, the majority of POLEmut subtypes showed the inflamed phenotype and all p53abn subtypes showed the non-inflamed phenotype, while three immunophenotypes were observed in MMRd and NSMP subtypes, although there was a significant distribution bias. The RNA-seq data showed that the expression of MYC target genes and type-1 interferon response genes was enriched in the non-inflamed phenotype in MMRd and NSMP subtypes respectively. Conclusion Evaluating not only the molecular classification but also the immunophenotype may lead to more personalized immunotherapy in EC and elucidating the mechanisms that underlie the formation of the three immunophenotypes could lead to the discovery of new immunotherapy targets.