A melanoma immune response signature including Human Leukocyte Antigen‐E

Abstract

Paired cultures of early-passage melanoma cells and melanocytes were established from metastatic lesions and the uninvolved skin of five patients. In this stringent autologous setting, cDNA profiling was used to analyze a subset of 1477 genes selected by the Gene Ontology term 'immune response'. Human Leukocyte Antigen E (HLA-E) was ranked 19th among melanoma-overexpressed genes and was embedded in a transformation signature including its preferred peptide ligand donors HLA-A, HLA-B, HLA-C, and HLA-G. Mostly undetectable in normal skin and 39 nevi (including rare and atypical lesions), HLA-E was detected by immunohistochemistry in 17/30 (57%) and 32/48 (67%) primary and metastatic lesions, respectively. Accordingly, surface HLA-E was higher on melanoma cells than on melanocytes and protected the former (6/6 cell lines) from lysis by natural killer (NK) cells, functionally counteracting co-expressed triggering ligands. Although lacking HLA-E, melanocytes (4/4 cultures) were nevertheless (and surprisingly) fully protected from NK cell lysis.

HLA‐E allelic genotype correlates with HLA‐E plasma levels and predicts early progression in chronic lymphocytic leukemia

“…In patients with colorectal cancer, the overexpression of HLA‐E molecules associated with β2‐microglobulin was reported as a surrogate marker of a poor prognosis and a novel mechanism of tumor immune escape, whereas 1 study described high HLA‐E expression in long‐term survivors of cervical adenocarcinomas . Conversely, independent groups noticed that HLA‐E surface expression was observed on malignant melanoma cells, but not on healthy skin . Increased levels of sHLA‐E molecules were observed in the circulation of patients with melanoma, which introduced sHLA‐E as a potential immune‐related biomarker in cancer .…”

“…30 Conversely, independent groups noticed that HLA-E surface expression was observed on malignant melanoma cells, but not on healthy skin. 31,32 Increased levels of sHLA-E molecules were observed in the circulation of patients with melanoma, which introduced sHLA-E as a potential immune-related biomarker in cancer. 31,33 Mechanistically, sHLA-E is able to induce apoptosis in T and NK cells by a Fas/Fas ligand-mediated pathway.…”

Monoclonal antibodies to HLA‐E bind epitopes carried by unfolded β2m‐free heavy chains

“…The MEM mAbs were characterized by at least three groups [6,[8][9][10][11]. We found that they selectively bind unfolded HLA-E heavy chains free of β 2 m. Whereas mAb MEM-E/02 was particularly restricted to HLA-E in IEF/Western blotting, mAbs MEM-E/07 and MEM-E/08 cross-reacted to different extents with detergent-soluble HLA-A, -B, -C heavy chains, suggesting recognition of three distinct, although unmapped, nonconformational epitopes [6,12,13]. In contrast, using microbeads carrying HLA-E and HLA-A, -B, -C molecules, Ravindranath et al mapped mAbs MEM-E/02, MEM-E/07 and 3D12 to the same discontinuous, conformational, widely HLA-B/-C-cross-reactive epitope [8][9][10], and concluded that all these mAbs (particularly mAb MEM-E/08) are suitable to bind "intact HLA-β 2 m complexes."…”

“…In our previous flow cytometry studies [6,[12][13][14], HLAhomozygous cell lines reacted with the MEM mAbs weakly and regardless of the coexpressed, and putatively cross-reactive [6], HLA-A, -B, -C alleles. Therefore, the cross-reactivity on HLA microbeads and the much weaker and restricted one detected in detergent lysates (Fig.…”

Modulation of MHC class I surface expression in B16F10 melanoma cells by methylseleninic acid

“…While the expression of HLA-A, -B and -C antigens are frequently lost or downregulated on tumor cells, HLA-G and/or HLA-E antigens are often overexpressed in tumors of distinct origin, e.g., ovarian carcinoma, colon carcinoma and melanoma. [27][28][29] Since HLA-E can bind to the inhibitory CD94/NKG2A receptors expressed on NK cells and a subset of T cells, HLA-E expression could lead to an escape of tumor cells from immune surveillance. 30 Interestingly, the selenocompound selenite is able to reduce HLA-E antigen expression in different tumor cells, which was accompanied by an enhanced NK cell-mediated killing 31 suggesting that selenite might be able to potentiate the antitumor cytotoxicity in settings of NK cell-based immunotherapies.…”