Tumor immune microenvironment in endometrial cancer of different molecular subtypes: evidence from a retrospective observational study

OBJECTIVE: Tumor immune microenvironmental features may predict survival and guide treatment. This study aimed to comprehensively decipher the immunological features of different molecular subtypes of endometrial cancer. METHODS: In this retrospective study, 26 patients with primary endometrial cancer and four with recurrent disease treated in our center from December 2018 to November 2021 were included. Next-generation sequencing was performed on tumor samples. Patients were classified into four subtypes, including POLE mutant, microsatellite instability high (MSI-H), no specific molecular profile (NSMP) and TP53 mutant subtypes. Tumor-infiltrating immune cells were quantified using multiplex immunofluorescence assays. RESULTS: Of the 26 primary endometrial cancer cases, three were POLE mutant, six were MSI-H, eight were NSMP and nine were TP53 mutant. Of the four recurrent cases, two belonged to the NSMP subtype and two belonged to the TP53 mutant subtype. The tumor mutation burden (TMB) levels of POLE mutant and MSI-H cases were significantly higher than that of the other two subtypes (p< 0.001). We combined POLE mutant and MSI-H subtypes into the TMB high (TMB-H) subtype. The TMB-H subtype showed a high degree of infiltration of CD8(+) T cells. In the NSMP subtype, the overall degree of intra-tumoral infiltrating immune cells was low. In the TP53 mutant subtype, the densities of both PD-L1(+) macrophages (p = 0.047) and PD-1(+) T cells (p = 0.034) in tumor parenchyma were the highest among the four subtypes. CONCLUSION: Endometrial cancer of TMB-H, NSMP and TP53 mutant subtypes displayed phenotypes of normal immune response, absence of immune infiltration, and suppressed immune response, respectively. These features may provide mechanistic explanations for the differences in patients’ prognosis and efficacy of immune checkpoint blockade therapies among different endometrial cancer subtypes.