Melanoma Stem Cell-Like Phenotype and Significant Suppression of Immune Response within a Tumor Are Regulated by TRIM28 Protein

Abstract

Simple Summary

A growing body of evidence indicates that stem cell-associated molecular features, collectively known as stemness, are biologically important in cancer development and progression, and negatively associate with anticancer immunity. The aim of our study was to investigate the association between TRIM28 level and melanoma stemness accompanied by low antitumor immune response. Furthermore, we aimed to evaluate potential value for TRIM28 in predicting stem-like melanoma phenotype. Our results indicate that TRIM28 might facilitate the “stemness high/immune low” melanoma phenotype by attenuating interferon signaling leading to a worse prognosis for melanoma patients. TRIM28 emerged as a regulator Interferon Regulatory Factor family of transcription factors’ expression, mediating epigenetic repression of IRF family members in “stemness high/immune low” melanomas.

Abstract

TRIM28 emerged as a guard of the intrinsic “state of cell differentiation”, facilitating self-renewal of pluripotent stem cells. Recent reports imply TRIM28 engagement in cancer stem cell (CSC) maintenance, although the exact mechanism remains unresolved. TRIM28 high expression is associated with worse melanoma patient outcomes. Here, we investigated the association between TRIM28 level and melanoma stemness, and aligned it with the antitumor immune response to find the mechanism of “stemness high/immune low” melanoma phenotype acquisition. Based on the SKCM TCGA data, the TRIM28 expression profile, clinicopathological features, expression of correlated genes, and the level of stemness and immune scores were analyzed in patient samples. The biological function for differentially expressed genes was annotated with GSEA. Results were validated with additional datasets from R2: Genomics Analysis and Visualization Platform and in vitro with a panel of seven melanoma cell lines. All statistical analyses were accomplished using GraphPad Prism 8. TRIM28 ^HIGH-expressing melanoma patients are characterized by worse outcomes and significantly different gene expression profiles than the TRIM28 ^NORM cohort. TRIM28 high level related to higher melanoma stemness as measured with several distinct scores and TRIM28 ^HIGH-expressing melanoma cell lines possess the greater potential of melanosphere formation. Moreover, TRIM28 ^HIGH melanoma tumors were significantly depleted with infiltrating immune cells, especially cytotoxic T cells, helper T cells, and B cells. Furthermore, TRIM28 emerged as a good predictor of “stemness high/immune low” melanoma phenotype. Our data indicate that TRIM28 might facilitate this phenotype by direct repression of interferon signaling. TRIM28 emerged as a direct link between stem cell-like phenotype and attenuated antitumor immune response in melanoma, although further studies are needed to evaluate the direct mechanism of TRIM28-mediated stem-like phenotype acquisition.