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

描述（申请人提供）：该提议的目的是检验以下假设：（i）尽管限制性HLA I类等位基因和靶TA表达，但缺乏HLA I类抗原限制的肿瘤抗原（TA）特异性细胞毒性T淋巴细胞（CTL）对头颈部鳞状细胞癌（SCCHN）细胞的识别，反映HLA I类等位基因-TA衍生肽复合物的缺陷（ii）这些缺陷由抗原加工机制（ARM）组分的表达和/或功能降低引起，（iii）HLA I类-TA肽复合物表达和SCCHN细胞识别受HLA I类抗原限制，TA特异性CTL可通过纠正ARM组分缺陷而恢复，并且（iv）这些缺陷具有临床意义。这些假设源于以下观察结果：ARM组分下调（i）已在SCCHN细胞中观察到，并且与缺乏它们被HLA I类抗原限制性的TA特异性CTL识别有关，（ii）可在体外被IFN-γ校正，导致SCCHN细胞被HLA I类抗原限制性的TA特异性CTL识别，以及（iii）在疾病的临床过程中起作用。为了验证我们的假设，我们将SCCHN细胞中ARM组分的水平与HLA I-TA类肽复合物的水平以及与HLA I-TA类肽复合物特异性CTL的识别相关联。此外，我们还将研究ARM组分调节对SCCHN细胞表达HLA I类-TA肽复合物及其被CTL识别的影响。最后，为了评估体外数据的体内意义，我们将测试i）IFN-γ施用是否增强HLA I类抗原限制性TA肽特异性CTL控制SCID小鼠中SCCHN肿瘤生长的能力，和ii）SCCHN病变中的ARM组分、HLA I类抗原和HLA I-TA肽复合物表达是否与其组织病理学和/或临床过程相关。所提出的研究利用了一组独特的ARM组分特异性mAb，我们已经开发了定量细胞中ARM组分水平的方法以及HLA-A2-HER 2369 -377和HLA-A2-法师-3/627 i-279特异性scFv片段。概述的研究i）可以鉴定新的生物标志物以监测SCCHN患者的疾病，和ii）将有助于表征癌症患者中疾病进展的潜在机制，尽管在其恶性病变中存在HLA I-TA类肽复合物特异性CTL和HLA I类抗原表达。

DESCRIPTION (provided by applicant): 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.