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

这项提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(SCCHN)细胞受HLAI类抗原限制，肿瘤抗原(TA)特异性细胞毒 T淋巴细胞(CTL)，尽管限制了HLAI类等位基因和靶TA的表达，但反映了 人类白细胞抗原I类等位基因-TA衍生多肽复合体(HLAI-TA多肽复合体)的表达，(Ii)这些 缺陷是由抗原处理机制(ARM)的表达和/或功能降低引起的 HLAI-TA多肽复合体的表达及其对SCCHN细胞的识别作用 抗原受限的TA特异性CTL可以通过纠正手臂组件缺陷来恢复，以及(Iv)这些 缺陷具有临床意义。这些假设源于对ARM组件的观察 在SCCHN细胞中观察到下调(I)，并与其缺乏被人类白细胞抗原识别有关 I类抗原限制性的TA特异性CTL，(Ii)可在体外被干扰素-γ纠正，导致识别 SCCHN细胞受HLAI类抗原限制的TA特异性CTL和(III)在急性髓细胞白血病的临床病程中的作用 这种疾病。为了检验我们的假设，我们将SCCHN细胞中ARM组件的水平与 并被HLAI-TA多肽复合体特异性CTL识别。 此外，我们还将研究ARM成分调控对人类白细胞抗原I-TA类多肽复合体的影响 SCCHN细胞的表达及其对CTL的识别作用。最后，为了评估在体内的意义， 在体外数据中，我们将测试i)干扰素-γ是否增强了人类白细胞抗原I类抗原的能力。 用于控制SCID小鼠SCCHN肿瘤生长的限制性TA多肽特异性CTL和II)臂成分， SCCHN皮损中HLAI类抗原和HLAI-TA多肽复合体的表达与其相关性 组织病理学和/或临床病程。拟议的研究利用了一种独特的ARM组件面板- 特异性单抗，我们开发的方法来定量细胞中的ARM成分水平和人类白细胞抗原-A2- HER2369-377和HLAA2-MAGE-3/627I-279特异性单链抗体片段。概述的研究I)可以识别小说 监测SCCHN和II患者疾病的生物标志物将有助于表征 尽管存在HLAI-TA，癌症患者疾病进展的机制(S) 多肽复合体特异性CTL和HLAI类抗原在其恶性病变中的表达

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.