The muscle excess 3 (MEX-3) protein was first identified in Caenorhabditis elegans (C. elegans), and its respective homologues were also observed in vertebrates, including humans. It is a RNA-binding protein (RBP) with an additional ubiquitin E3 ligase function, which further acts as a post-transcriptional repressor through unknown mechanisms. In humans, MEX-3 proteins post-transcriptionally regulate a number of biological processes, including tumor immunological relevant ones. These have been shown to be involved in various diseases, including tumor diseases of distinct origins. This review provides information on the expression and function of the human MEX-3 family in healthy tissues, as well after malignant transformation. Indeed, the MEX-3 expression was shown to be deregulated in several cancers and to affect tumor biological functions, including apoptosis regulation, antigen processing, and presentation, thereby, contributing to the immune evasion of tumor cells. Furthermore, current research suggests MEX-3 proteins as putative markers for prognosis and as novel targets for the anti-cancer treatment.

Progression of oral squamous cell carcinoma (OSCC) has been associated with an escape of tumor cells from the host immune surveillance due to an increased knowledge of its underlying molecular mechanisms and its modulation by the tumor microenvironment and immune cell repertoire. In this study, the expression of HLA class I (HLA-I) antigens and of components of the antigen processing machinery (APM) was analyzed in 160 pathologically classified human papilloma virus (HPV)-negative OSCC lesions and correlated to the intra-tumoral immune cell response, IFN-γ signaling and to the patient’s outcome. A heterogeneous but predominantly lower constitutive protein expression of HLA-I APM components was found in OSCC sections when compared to non-neoplastic cells. Tumoral HLA-I APM component expression was further categorized into the three major phenotypes HLA-I^high/APM^high, HLA-I^low/APM^low and HLA-I^{discordant high/low}/APM^high. In the HLA-I^high/APM^high group, the highest frequency of intra-tumoral CD8⁺ T cells and lowest number of CD8⁺ T cells close to FoxP3⁺ cells were found. Patients within this group presented the most unfavorable survival, which was significantly evident in stage T2 tumors. Despite a correlation with the number of intra-tumoral CD8⁺ T cells, tumoral JAK1 expression as a surrogate marker for IFN-γ signaling was not associated with HLA-I/APM expression. Thus, the presented findings strongly indicate the presence of additional factors involved in the immunomodulatory process of HPV-negative OSCC with a possible tumor-burden-dependent complex network of immune escape mechanisms beyond HLA-I/APM components and T cell infiltration in this tumor entity.

Background: The human leukocyte antigen (HLA) class II molecules are constitutively expressed in some melanoma, but the underlying molecular mechanisms have not yet been characterized. Methods: The expression of HLA class II antigen processing machinery (APM) components was determined in melanoma samples by qPCR, Western blot, flow cytometry and immunohistochemistry. Immunohistochemical and TCGA datasets were used for correlation of HLA class II expression to tumor grading, T-cell infiltration and patients’ survival. Results: The heterogeneous HLA class II expression in melanoma samples allowed us to characterize four distinct phenotypes. Phenotype I totally lacks constitutive HLA class II surface expression, which is inducible by interferon-gamma (IFN-γ); phenotype II expresses low basal surface HLA class II that is further upregulated by IFN-γ; phenotype III lacks constitutive and IFN-γ controlled HLA class II expression, but could be induced by epigenetic drugs; and in phenotype IV, lack of HLA class II expression is not recovered by any drug tested. High levels of HLA class II APM component expression were associated with an increased intra-tumoral CD4+ T-cell density and increased patients’ survival. Conclusions: The heterogeneous basal expression of HLA class II antigens and/or APM components in melanoma cells is caused by distinct molecular mechanisms and has clinical relevance.