Immune signatures of the POLE mutation in endometrial carcinomas: a systematic study based on TCGA data and clinical cohort validation

Abstract

BackgroundPOLE is a critical biomarker for endometrial cancer (ECs) prognosis and therapeutic decision. However, the immune infiltration and immunotherapy-related gene expression in the tumor microenvironment (TME) of POLE-mutated ECs remain unresolved.MethodsThe TCGA database was used to characterize the TME of POLE mutants, which primarily included immune cells and co-expression genes. We used immunohistochemistry (IHC) to determine immune cell abundance and PD-L1 expression in 104 EC tissues, including 11 POLE mutants and 93 wild-type.ResultsThe bioinformatic study found significant differences in gene expression of the chemokine family, immune-cell markers, and lysozyme in POLE mutants, along with immune response activation. In POLE-mutated ECs, the abundance of CD4+T, CD8+T, M1 macrophages, and dendritic cells increased considerably. Furthermore, POLE mutations may enhance immune cell recruitment or activation and lymphocyte homing in ECs. POLE mutants also had increased expression of immune-checkpoint suppressor genes such as PD-L1, CTLA-4, TIM-3, and others. The tumor mutation burden (TMB) was higher in ECs with POLE mutation. In the validation cohort, we discovered that POLE mutations were related to the immune infiltration abundance of CD8+, CD4+, and Foxp3+ cells and PD-L1 expression by IHC. The prognosis of TCGA-ECs showed that the survival time of the CD8, CD4, PD-L1, or Foxp3 over-expression subgroup of the POLE mutants was significantly prolonged compared to the down-regulation subgroup or the POLE wild-type.ConclusionThe infiltration abundance of CD8+ T, CD4+ T, Foxp3+ T cells, and the expression of PD-L1 harbor crucial value for the prognosis or individualized therapy of POLE-mutated ECs.

The Clinical and Pathological Characteristics of POLE-Mutated Endometrial Cancer: A Comprehensive Review

“…26 Furthermore, within POLE-mutated ECs, there is an upregulation of immune checkpoint molecules and regulatory T cell markers, including LAG3, TIM-3, TIGIT, PD-1, CTLA-4, and FOXP3, potentially as a result of immune evasion caused by prolonged exposure to antigens. 27 This implies that immune checkpoint inhibitors hold potential for a subset of patients with recurrent or metastatic POLE-mut ECs. [27][28][29][30][31] Nevertheless, the factors contributing to the absence of heightened immune responses in certain POLE-mut patients remain unclear, including whether it is attributed to a low mutation burden or other immune evasion mechanisms.…”

“…27 This implies that immune checkpoint inhibitors hold potential for a subset of patients with recurrent or metastatic POLE-mut ECs. [27][28][29][30][31] Nevertheless, the factors contributing to the absence of heightened immune responses in certain POLE-mut patients remain unclear, including whether it is attributed to a low mutation burden or other immune evasion mechanisms. A study examining early-stage low-grade EC identified five distinct immunotypes that exhibited superior sensitivity and specificity in predicting recurrence.…”