Molecular-based analysis of HLA class I processing machinery defects in human melanoma

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One of the large concerns in melanoma T cell based immunotherapy is the immune escape phenomenon resulting from loss of melanoma associated antigens and/or HLA class I. The head investigator has been analyzing the mechanisms of down regulation of HLA class I in melanocytic cells.In the present study, molecular-based analysis of HLA class I processing machinery defects in human melanoma was investigated using monoclonal antibodies to melanoma associated antigens (MART-1, gp100, tyrosinase), to molecules associated with antigen processing machinery (TAP-1, TAP-2, LMP-2, LMP-7, LMP-10, Z, Delta, Tapacin, Calnexin, Calreticulin), and to HLA class I (HLA class I-heavy chain, HLA class I-light chain). The head investigator already found the antigen-retrieval method for all these monoclonal antibodies in formalin-fixed, paraffin-embedded tissue sections.The head investigator found the following points :1)Melanoma associated antigens (MART-1, gp100, tyrosinase) were expressed highly in primary … More melanoma lesions. However, these expressions were down regulated in some metastatic melanoma lesions, especially in the lesions with low melanin content.2)Among the molecules associated with antigen processing machinery, delata and calreticulin were ubiquitously expressed in primary and metastatic lesions. Expression of TAP-1 and TAP-2 were remarkably down regulated especially in metastatic lesions.3)Expression of HLA class I heavy chain and light chain were remarkably down regulated in metastatic lesions.4)There was a close association between HLA class I and TAP-1/TAP-2 down regulation.5)There was an inverse association between CD8 infiltration and HLA class I down regulation.These data suggest that HLA class I expression is necessary for presenting melanoma associated antigens to CD8 T cells and TAP-1 and TAP-2 are most involved molecules in HLA class I down regulation. Also these data suggest that abnormality of these molecules are associated with immune escape mechanism in human melanoma. Less