The goals of this proposal are to test the hypotheses 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 the restricting HLA class I allele and target TA expression, reflects defects in HLA class I allele-TA derived peptide complex (HLA class I-TA peptide complex) expression, (ii) these defects are caused by decreased expression and/or function of antigen processing machinery (ARM) components, (iii) HLA class I-TA peptide complex expression and SCCHN cell recognition by HLA class I antigen restricted, TA-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 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-TA peptide complexes and with recognition by HLA class I-TA peptide complex-specific CTL. In addition, we will investigate the effect of ARM component modulation on HLA class I-TA peptide complex expression by SCCHN cells and on their recognition by CTL. Lastly, to assess the in vivo significance of the in vitro data, we will test whether i) IFN-y administration enhances the ability of HLA class I antigen restricted, TA peptide-specific CTL to control SCCHN tumor growth in SCID mice and ii) ARM component, HLA class I antigen and HLA class I-TA peptide complex expression in SCCHN lesions correlate with their histopathology and/or clinical course. The proposed studies utilize a unique panel of ARM component- specific mAb, methodology we have developed to quantitate ARM component levels in cells and HLA-A2- HER2369-377 and HLA-A2-MAGE-3/627i-279-specific scFv fragments. The outlined studies i) may identify novel biomarkers to monitor disease in patients with SCCHN and ii) will contribute to characterize the mechanism(s) underlying disease progression in cancer patients in spite of the presence of HLA class I-TA peptide complex-specific CTL and HLA class I antigen expression in their malignant lesions. ? ?
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