Tumor immune escape: Molecular mechanisms and counteracting strategies
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Changes in HLA class I antigen and NK cell-activating ligand expression have been identified in malignant lesions. These changes are believed to play a major role in the clinical course of the disease since both HLA class I antigens and NK cell-activating ligands are critical to the interaction between tumor cells and components of both innate and adaptive immune systems. In this study, novel molecular mechanisms underlying HLA class I antigen abnormalities have been identified in melanoma cells derived from malignant melanoma lesions. They include multiple hot-spot CT deletions in the β 2 m gene, selective HLA-A2 allospecificity loss, and antigen processing machinery component downregulation, which underlie a HLA class I antigen loss phenotype, as well as single amino acid substitution-carrying, loss-of-function β 2 m and combined germline/somatic tapasin gene mutations along with selective epigenetic inactivation of HLA-A locus IFN-γ responsiveness, which underlie a HLA class I antigen downregulaiton phenotype. The role of NK cell-activating ligand changes in melanoma immune escape is indicated by the markedly reduced sensitivity to NK cell-mediated lysis in vitro of two of four HLA class I - melanoma cell lines because of their lack of expression of MICA, a ligand for the NKG2D activating receptor. These MHC defects have potential negative impact on both cytotoxic T lymphocyte- and NK cell-mediated anti-tumor responses and thus prompted the development of active specific cancer immunotherapy targeting non-MHC molecules. To this end, the three-dimensional structural basis of tumor antigen mimicry by an anti-idiotypic (id) antibody has been elucidated at the atomic level in the high molecular weight-melanoma associated antigen (HMW-MAA) system. A single complementarity-determining region loop of anti-id antibody MK2-23, which carries the internal image of the nominal HMW-MAA epitope, represents a useful system to investigate which extent of antigen mimicry would maximize the immunogenicity of an antigen mimic. Taken together, the results of my study advance our understanding of the mechanisms underlying the lack of immune control of clinically evident tumors and contribute to the development of alternative cancer immunotherapeutic strategies.