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

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

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Abstract

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