Molecular abnormalities in the expression of HLA class-I antigens by melanoma cells

Abstract

Testing of a panel of cultured human melanoma cells with radiolabelled anti-HLA-class4 monoclonal antibodies (MAbs) in a binding assay has shown lack of reactivity of FO-I and SK-MEL-33 cells and low reactivity of SK-MEL-I9 cells. SDS-PAGE analysis of the components immunoprecipitated from the 3 intrinsically radiolabelled melanoma cell lines by antibodies to the 2 subunits of HLA-class4 antigens has not detected p2-p in the immunoprecipitates from melanoma cells FO-I and SK-MEL-33 and only a low level of HLA-class4 heavy chain in the immunoprecipitate from SK-MEL-19 cells.Northern blotting analysis with probes specific for HLA-class4 heavy chain and for p2-p indicates that the abnormalities in HLA-class-I-antigen expression reflects a defect at the transcriptional level in The potential role of the immune system in the pathogenesis and clinical course of melanoma (Balch et al., 1989) has stimulated interest in the characterization of HLA-class4 and class-11-antigen expression by melanoma cells. Immunohistochemical staining of a large number of surgically removed melanoma lesions has shown reduction or loss of HLA class-I-antigen expression in about 10% of the primary lesions and in about 30% of metastatic lesions (Ruiter et al., 1991). Because of the role of HLA-class-I antigens in the recognition of target cells by cytotoxic T cells (McMichael, 1980) and by NK cells (Ljunggren and Karre, 1990), these changes are likely to affect the interaction of melanoma cells with the host's immune system. The potential clinical significance of reduced HLAclass-I-antigen expression by melanoma cells is suggested by the statistically significant, although not absolute, association between low level of HLA-class-I antigens in melanoma lesions and poor clinical course of the disease (Van Duinen et al., 1988). The molecular abnormalities underlying the defects in HLA-class-I-antigen expression by melanoma cells have been characterized only to a limited extent (Versteeg et al., 1988; D'Urso et al., 1991), although this information contributes to our understanding of the regulatory mechanisms controlling HLAclass-I-antigen synthesis and membrane insertion and is required to develop approaches to correct reduction or lack of HLA-class-I-antigen expression by melanoma cells. The latter may have therapeutic implications, if abnormalities in the HLA-class-I-antigen expression are proven to play a role in the clinical course of the disease.In previous reports we have described the expression of HLA-class-I and class-I1 antigens by melanoma cell lines in long-term culture and in surgically removed melanoma lesions. In the present report, we describe the molecular defects which underlie abnormalities in HLA-class-I-antigen expression by 3 melanoma cell lines. MATERIAL AND METHODSThe growth conditions of cell lines, the characteristics of monoclonal and polyclonal antibodies and the methodology to perform serological and immunochemical assays and RNA hybridization analysis have been described elsewhere (D'Urso et al., 1991). RESULTSTestin...

Ex vivo activated memory t‐lymphocytes as adoptive cellular therapy of human soft‐tissue sarcoma targets with potentiation by Cis‐diamminedichloroplatinum (II)

“…The mechanism of this synergistic effect by CDDP is not clear but may be secondary to drug-induced alteration of the tumor target cell membrane, rendering it more susceptible to effector cell attack. It has been postulated that one mechanism of development of tumor metastases may be immune-mediated escape or nonrecognition of tumor targets by host immune cells [41,42]. Indeed, an elegant study by Alexander et al [43] showed that advanced but not early stage melanoma had defective antigen-presentation capability.…”

“…This may explain why PBL from MSTS-5 demonstrated some lysis against PSTS-4. Down-regulation of MHC class I antigens on sarcomas may allow tumors to immunologically evade host defenses [41,42]. Some patients with HLA-A2+ disseminated melanomas that were successfully treated with ALT-cells and CY were able to demonstrate ex vivo lysis of allogeneic HLA-A2+ melanomas but not HLA-A2-melanomas [5].…”

About the cutaneous targets of bexarotene in CTCL patients

“…ICAM‐1 is expressed by a large variety of non‐hematopoietic cells such as keratinocytes (21), and is the ligand for leucocyte function associated antigen‐1 (LFA‐1): this non‐antigen specific system is considered to be crucial in the adhesion between lymphocytes and antigen‐presenting cells, endothelial cells or target cells (22). Retinoic acid‐responsive elements have been found in the 5′‐regulatory region of the human ICAM‐1 gene (23), and RA‐induced ICAM‐1 up‐regulation on the cell surface of various cell lines has already been reported, such as human thyroid cells or melanoma cell‐lines (24–26).…”

The human leukocyte antigen TAP2 gene defines the centromeric limit of melanoma susceptibility on chromosome 6p

“…reduction in class I has not been defined (40). Finally, allelic variants of TAP2 (in the rat) discriminate classes of peptides for transport thereby conferring specificity to the process of antigen presentation (5).…”