Elevation of c-MYC Disrupts HLA Class II–Mediated Immune Recognition of Human B Cell Tumors

Abstract

Elevated levels of the transcription factor c-myc are strongly associated with various cancers, and in particular B-cell lymphomas. While many of c-MYC’s functions have been elucidated, its effect on the presentation of antigen (Ag) through the HLA class II pathway has not previously been reported. This is an issue of considerable importance, given the low immunogenicity of many c-MYC-positive tumors. We report here that increased c-MYC expression has a negative effect on the ability of B-cell lymphomas to functionally present Ags/peptides to CD4+ T cells. This defect was associated with alterations in the expression of distinct co-factors as well as interactions of antigenic peptides with class II molecules required for the presentation of class II-peptide complexes and T cell engagement. Using early passage Burkitt’s lymphoma (BL) tumors and transformed cells, we show that compared to B-lymphoblasts, BL cells express decreased levels of the class II editor HLA-DM, lysosomal thiol-reductase GILT, and a 47kDa enolase-like protein. Functional Ag presentation was partially restored in BL cells treated with a c-MYC inhibitor, demonstrating the impact of this oncogene on Ag recognition. This restoration of HLA class II-mediated Ag presentation in early passage BL tumors/cells was linked to enhanced HLA-DM expression and a concurrent decrease in HLA-DO in BL cells. Taken together, these results reveal c-MYC exerts suppressive effects at several critical checkpoints in Ag presentation which contribute to the immunoevasive properties of BL tumors.

HLA class II antigen-processing pathway in tumors: Molecular defects and clinical relevance

“…Suppression of CIITA transcription mediated by the overexpression of HASH-1, c-Myc and N-Myc, which competitively bind to the E-box in the CIITA-PIV has been reported in neuroblastoma, in small cell lung carcinoma (SCLC) and in B-cell tumors. 49,50 In contrast, RET/PTC expression is correlated with increased CIITA expression associated with an increased HLA class II antigen expression. 51 The lack of STAT1a and the retinoblastoma tumor suppressor gene affects CIITA expression and consequently leads to an impaired constitutive and IFNg-inducible HLA class II antigen expression as demonstrated in breast carcinoma and NSCLC cells.…”

Cooperative Targets of Combined mTOR/HDAC Inhibition Promote MYC Degradation

“…The findings from the cell models led to the identification of decreased MYC stability as a major contributor to the cooperative inhibitory activity of the mTORi/HDACi combination. Although we focused our efforts on how decreased MYC protein levels ultimately led to decreases in many of the genes in our gene signature, presumably through decreased binding of their promoters, it is worth noting that the increase in Class II HLA could also be an indirect result of decreasing MYC levels (50). As such, the drug combination may also help to increase immune recognition by increasing antigen presentation.…”

Neuron specific enolase: a promising therapeutic target in acute spinal cord injury

“…Surface enolase can drive spinal microglial activation with upregulation of major histocompatibility complex-1 (MHC-1) and MHC-II [44, 45], which in turn may induce inflammatory responses after acute SCI. Our recent study suggests that an increased enolase expression enhances MHC-II-mediated antigen presentation by B-cells, macrophages, and dendritic cells, and also activates CD4+ T cells [46]. Studies have also found measurable NSE in cerebrospinal fluid (CSF) and serum, which is elevated in different inflammatory diseases involving neuronal destruction [47].…”