Analysis of tumor mutation burden combined with immune infiltrates in endometrial cancer

Abstract

Background: Tumor mutational burden (TMB) is widely regarded as a predictor of response to immunotherapy. Few researchers have focused on the activity and prognosis of TMB in endometrial cancer (EC) and immune cells. Our study aimed to identify the prognostic role of TMB in EC.Methods: We downloaded transcriptome data from The Cancer Genome Atlas (TCGA) database. Kaplan-Meier analysis with log-rank test was conducted to assess the difference in overall survival (OS) between the high and low TMB groups. The "CIBERSORT" scripts were performed to evaluate the immune compositions of EC patients. Cox regression analysis and survival analysis were used to verify the prognostic value prognosis of TMB.Results: We obtained the single nucleotide mutation data for 529 EC patients. A missense mutation was the most common mutation type. TMB was associated with survival outcome, tumor grades, and pathological types. We identified 10 hub TMB-related signature and found that elevated T-cell subsets infiltrating density in the high TMB group revealed improved survival outcomes. According to Kaplan-Meier analysis, T cells gamma delta and T cells regulatory were prognostic immune cells in EC samples. Moreover, many top gene set enrichment analysis (GSEA) results, including amino sugar and nucleotide sugar metabolism, nucleotide excision repair, or p53 signaling pathway, were enriched significantly with TMB level as phenotype.Conclusions: TMB is an important prognostic factor for EC, and TMB-related genes may be potential therapeutic targets for EC.

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

“…Previous studies have indicated that increased infiltration of intratumoral CD8 + T cells is associated with a better prognosis in different cancer types (36)(37)(38), and a recent study based on multiplex immunofluorescent assays further supported the prognostic value of tumor infiltrating T cells in early-stage endometrial cancer (39). In this study, we also observed relatively high percentages of CD8 + T cells in samples of TMB-H EC, which is believed to have a favorable survival outcome (23). However, studies have shown that the functional status of CD8 + T cells changes with tumor progression, and different stages of dysfunctional T cells, characterized by the expression of specific immune checkpoint molecules, are thought to be associated with distinct response rates to immune checkpoint inhibitors (40).…”

“…Consistent with TCGA data (1), patients with POLE mutations showed the highest level of TMB, followed by the MSI-H subtype, NSMP, and TP53 mutant subtypes (Figure 2). Recent studies have indicated that TMB is highly associated with tumor-infiltrating immune cells, PD-L1 expression, and patients' prognosis in both endometrial cancer and other cancer types (23)(24)(25). Additionally, considering the relatively small sample size of the POLE mutant and MSI-H subtypes, we combined the two subtypes into the TMB high (TMB-H) subtype in the following analysis.…”

Features of the immunosuppressive tumor microenvironment in endometrial cancer based on molecular subtype

“…The higher TMB and PD-L1 expression in MSI-H and MMRd endometrial tumors support the clinical efficacy of PD-1 inhibitors in treating solid tumors with MMRd (112). Moreover, as mentioned earlier, PD-L1 expression increased with TIL abundance in the EC ITME, indicating that PD-1 inhibitors can induce an effective anti-tumor immune response in EC with high PD-L1 expression (104)(105)(106). In 2017, the FDA approved pabolizumab for the treatment of solid tumors with unresectable or metastatic MSI-H or MMRd.…”

“…According to the TCGA data, patients with POLE mutations showed the highest tumor mutation burden (TMB), followed by those with the MSI-H subtype. Reports have illuminated that TMB is highly associated with tumorinfiltrating immune cells, PD-L1 expression and patients' prognosis in EC (104)(105)(106). Meanwhile, studies have also reported that POLEmut and MMRd EC have a high number of CD8+ CTLs expressing PD-1 (29).…”

MiRNA based tumor mutation burden diagnostic and prognostic prediction models for endometrial cancer

“…[ 13–15 ]. Recently, the role of TMB combined with immune infiltration in endometrial cancer was studied [ 16 ]. Micro ribonucleic acid (miRNA) is a type of non-coding RNA fragment that has the function of regulating the expression of post-transcribed genes.…”