Antigen processing and HLA-peptide complexes in head and neck cancer

本提案的目的是检验以下假设：（i）对鳞状细胞癌缺乏认识 通过HLA I类抗原限制的、肿瘤抗原（TA）特异性细胞毒性的头颈部（SCCHN）细胞 T淋巴细胞（CTL），尽管限制HLA I类等位基因和目标TA表达，反映了缺陷， HLA I类等位基因-TA衍生肽复合物（HLA I-TA肽复合物）表达，（ii）这些 缺陷是由抗原加工机制（ARM）的表达和/或功能降低引起的 （iii）HLA I类-TA肽复合物表达和由HLA I类识别的SCCHN细胞 抗原限制的TA特异性CTL可以通过纠正ARM组分缺陷来恢复，和（iv）这些 缺陷具有临床意义。这些假设源于对ARM组件 在SCCHN细胞中观察到下调（i），并且与缺乏HLA对其的识别有关 I类抗原限制的TA特异性CTL，（ii）可在体外被IFN-γ校正，导致识别 SCCHN细胞通过HLA I类抗原限制性的、TA特异性的CTL和（iii）在临床病程中起作用， 这种疾病为了检验我们的假设，我们将SCCHN细胞中ARM组分的水平与那些 的HLA I-TA类肽复合物和HLA I-TA类肽复合物特异性CTL的识别。 此外，我们还将研究ARM成分调节对HLA I类-TA肽复合物的影响 通过SCCHN细胞的表达和它们被CTL识别。最后，为了评估在体内的意义， 在体外数据中，我们将测试i）IFN-γ给药是否增强HLA I类抗原 控制scid小鼠中SCCHN肿瘤生长的限制性TA肽特异性CTL和ii）ARM组分， SCCHN病变中HLA I类抗原和HLA I类-TA肽复合物的表达与其 组织病理学和/或临床过程。拟议的研究利用了一个独特的ARM组件面板- 特异性mAb，我们已经开发了定量细胞和HLA-A2中ARM组分水平的方法。 HER2369 - 377和HLA-A2-法师-3/627 i-279特异性scFv片段。概述的研究i）可以确定新的 用于监测SCCHN患者疾病的生物标志物，以及ii）将有助于表征 尽管存在HLA I-TA类，但癌症患者疾病进展的潜在机制 肽复合物特异性CTL和HLA I类抗原表达。

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.