Dysregulated Expression of HLA Molecules, and Antigen Processing in Patients with

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The goals of this proposal are to test the hypothesis that (i) lack of recognition of squamous cell carcinoma of the head and neck (SCCHN) cells by HLA class I antigen restricted, tumor antigen (TA)-specific cytotoxic T lymphocytes (CTL), in spite of restricting HLA class I allele and TA expression, reflects defects in HLA class I antigen-TA peptide complex expression, (ii) these defects are caused by decreased expression and/or function of antigen processing machinery (ARM) components, which we are considering to include the ctglucosidases l/ll (Gl/ll) and (Hi) HLA class I -TA peptide complex expression and SCCHN cell recognition by HLA class I antigen restricted, TA peptide-specific CTL can be restored by correcting ARM component defects and (iv) these defects have clinical significance. These hypotheses stem from observations that ARM component downregulation (i) has been observed in SCCHN cells and is associated with lack of their recognition by HLA class I antigen restricted, TA-specific CTL, (ii) can be corrected in vitro by IFN-y resulting in recognition of SCCHN cells by can restore HLA class I-TA peptide complex expression as well as SCCHN cell recognition by HLA class I antigen restricted, TA-specific CTL and (iii) plays a role in the clinical course of the disease. To test our hypotheses, we will correlate levels of ARM components in SCCHN cells with those of HLA class I antigens and HLA class I-TA peptide complexes and recognition by HLA class I antigen restricted, TA peptide-specific CTL, as well as investigate the effect of ARM component modulation on HLA class I antigen-TA peptide complex expression by SCCHN cells and their recognition by CTL. To assess the clinical significance of our studies we will (i) correlate ARM component defects in SCCHN lesions with their histopathology and/or clinical course, and (ii) determine if intralesional administration of INF-y enhances ARM component and HLA class I-TA peptide complex expression SCCHN lesions. The proposed studies will utilize a unique panel of monoclonal antibody (mAb) which recognize all ARM components and methodology we have recently developed to quantitate the level of ARM component expression in cells and HLA-AHER2369- 377 and HLA-A2-MAGE-3/6271-279 peptide complexes. The results derived form the outlined studies will contribute to our understanding of the molecular mechanism(s) underlying the lack of recognition of SCCHN cells by HLA class I antigen restricted, TA peptide-specific CTL, assess the clinical relevance of ARM component and HLA class I-TA peptide complex defects, and may identify strategies to correct these abnormalities and impact on the clinical course of SCCHN.