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

这项建议的目标是检验以下假设：(I)缺乏对鳞状细胞癌的识别 头颈部(SCCHN)细胞受HLAI类抗原限制的肿瘤抗原(TA)特异性细胞毒T细胞 淋巴细胞(CTL)尽管限制了人类白细胞抗原I类等位基因和TA的表达，但反映了人类白细胞抗原I类的缺陷 抗原-TA多肽复合体表达，(Ii)这些缺陷是由于表达减少和/或 抗原处理机制(ARM)组件的功能，我们正在考虑将其包括ct葡萄糖苷酶 L/Ⅱ(Gl/Ⅱ)和(Hi)HLAI-TA类多肽复合体的表达及其对SCCHN细胞的识别作用 通过纠正ARM成分，可以恢复受HL A-I类抗原限制的TA多肽特异性CTL (4)这些缺陷具有临床意义。这些假说源于对 在SCCHN细胞中观察到组分下调(I)，并与其缺乏相关 由人类白细胞抗原I类抗原限制的TA特异性CTL的识别，(Ii)可通过产生的干扰素-γ在体外纠正 在识别SCCHN细胞时可以恢复HLAI-TA多肽复合体的表达 人类白细胞抗原I类抗原限制性TA特异性CTL的细胞识别在临床过程中的作用 这种疾病的危害。为了验证我们的假设，我们将SCCHN细胞中ARM组件的水平与 HLAI类抗原和HLAI-TA多肽复合体与HLAI类抗原的识别 限制性TA多肽特异性CTL，以及研究ARM成分调节对人类白细胞抗原(HLA)的影响 I类抗原-TA多肽复合体在SCCHN细胞中的表达及其CTL识别要评估 我们的研究的临床意义我们将(I)将SCCHN病变中的手臂组件缺陷与 他们的组织病理学和/或临床病程，以及(Ii)确定肿瘤内给予干扰素-γ是否增强 ARM组分和HLAI-TA类多肽复合体表达SCCHN病变。拟议的研究将 利用一组独特的单抗(MAb)识别所有手臂组件和方法 我们最近开发了定量检测ARM组件在细胞中的表达水平和人类白细胞抗原-AHER2369- 377和人类白细胞抗原A2-MAGE-3/6271-279多肽复合体。从概述中得出的结果 研究将有助于我们理解认知缺失的分子机制(S) 用人类白细胞抗原I类抗原限制性TA多肽特异性CTL诱导SCCHN细胞，评估其临床意义 ARM组件和HLAI-TA类多肽复合体缺陷，并可能确定纠正这些缺陷的策略 SCCHN的异常及其对临床病程的影响。

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.