Biglycan-mediated upregulation of MHC class I expression in HER-2/neu-transformed cells

Abstract

The extracellular matrix protein biglycan (BGN) has oncogenic or tumor suppressive potential depending on the cellular origin. HER-2/neu overexpression in murine fibroblasts and human model systems is inversely correlated with BGN expression. Upon its restoration BGN HER-2/neu fibroblasts were less tumorigenic in immune competent mice when compared to BGN HER-2/neu cells, which was associated with enhanced immune cell responses and higher frequencies of immune effector cells in tumors and peripheral blood. The increased immunogenicity of BGN HER-2/neu fibroblasts appears to be due to upregulated MHC class I surface antigens and reduced expression levels of transforming growth factor (TGF)-β isoforms and the TGF-β receptor 1 suggesting a link between BGN, TGF-β pathway and HER-2/neu-mediated downregulation of MHC class I antigens. Treatment of BGN HER-2/neu cells with recombinant BGN or an inhibitor of TGF-β enhanced MHC class I surface antigens in BGN HER-2/neu-overexpressing murine fibroblasts, which was mediated by a transcriptional upregulation of major MHC class I antigen processing components. Furthermore, BGN expression in HER-2/neu cells was accompanied by an increased expression of the proteoglycan decorin (DCN). Since recombinant DCN also elevated MHC class I surface expression in BGN HER-2/neu cells, both proteoglycans might act synergistically. This was in accordance with analyses of mRNA data obtained from The Cancer Genome Atlas (TCGA) dataset available for breast cancer (BC) patients. Thus, our data provide for the first time evidence that proteoglycan signatures are modulated by HER-2/neu and linked to MHC class I-mediated immune escape associated with an altered TGF-β pathway.

Clinical and Biological Subtypes of B-cell Lymphoma Revealed by Microenvironmental Signatures

“…Proteoglycans did not show a statistically significant anti-proliferative effect in isolated PDX-derived lymphoma cells. Although there was no evidence of direct incorporation of the administered proteoglycans into the PDTX ECM, BGN administration resulted, as previously described (44), in 20% increase in DCN content (p = 0.032, vs. vehicle) in the PDTX2 ECM. Overall, this suggest that the anti-proliferative effect of these proteoglycans results from both short-and longrange interactions.…”

Identification of a novel miR‐21‐3p/TGF‐β signaling‐driven immune escape via the MHC class I/biglycan axis in tumor cells

“…BGN is modulated by and can modulate the TGF-β pathway by regulating the expression/activity of SMAD family members. 3 TGF-β treatment of the murine in vitro models and human BC cell lines caused a significantly enhanced miR-21-3p expression in BGN low HER-2/neu + cells, a heterogeneous increase in BC cell lines, but only a marginal upregulation in BGN high HER-2/neucells ( Figure S2). SMAD2 expression is downregulated in BGN low HER-2/neu + cells, but significantly enhanced in BGN-transfected HER-2/neu + cells (Figure 2A).…”

“…1,2 Recently, we have shown that HER-2/neu transformation resulted in a downregulation of BGN, causing a reduced MHC class I surface expression. 3 However, a relationship between miR-21-3p overexpression, enhanced TGF-β signaling, impaired BGN, and MHC class I expression in HER-2/neu + cells has not yet been investigated.…”

HLA Class I Antigen Processing Machinery Defects in Cancer Cells—Frequency, Functional Significance, and Clinical Relevance with Special Emphasis on Their Role in T Cell-Based Immunotherapy of Malignant Disease

“…Emerging evidence suggests key roles of tumor extracellular matrix (ECM) components and their proteolytic remodeling products in regulating the cancer-immunity cycle [103]. Indeed, the small leucine rich proteoglycan family member biglycan (BGN) has recently been associated with an altered MHC class I expression [104]. BGN expression could be downregulated by oncogenic transformation [105].…”