Novel immunogenic HLA-A*0201-restricted epidermal growth factor receptor-specific T-cell epitope in head and neck cancer patients.
Novel immunogenic HLA-A*0201-restricted epidermal growth factor receptor-specific T-cell epitope in head and neck cancer patients.
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DOI：
10.1097/cji.0b013e3181b8f421
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发表时间：
2010-01
期刊：
影响因子：
--
通讯作者：
Ferris RL
中科院分区：
文献类型：
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作者：
Andrade Filho PA;López-Albaitero A;Gooding W;Ferris RL
表皮生长因子受体 (EGFR) 高度过度表达，与结直肠癌和头颈鳞状细胞癌 (SCCHN) 的不良预后相关，针对表皮生长因子受体 (EGFR) 的治疗已显示出使用阻断性单克隆抗体、西妥昔单抗或帕尼单抗的临床疗效，但仅对 10% 至 20% 的患者有效。临床反应性与某些 Fcγ 受体基因型相关，表明免疫活性可能有助于治疗效果。此外，西妥昔单抗耐药的肿瘤细胞表现出 EGFR 的泛素化和降解，这将增加其作为细胞毒性 T 淋巴细胞 (CTL) 裂解的肿瘤抗原的加工。因此，基于 T 细胞的免疫疗法可能会增强 EGFR 特异性 mAb 的抗肿瘤功效，但 CTL 表位的定义却很差。为了允许组合 EGFR 靶向免疫治疗，我们鉴定了一种新型免疫原性野生型序列肽 EGFR853 – 861，并修改了其锚定序列以增强 HLA-A*0201 结合和刺激交叉反应性抗野生型 EGFR853 – 861 特异性 CTL。还观察到与 HER2861 – 869 的交叉反应性。通过将肿瘤细胞与西妥昔单抗一起孵育，EGFR853 – 861 对 SCCHN 细胞的特异性 CTL 识别增加，从而导致 EGFR 降解。此外，与健康对照外周血单核细胞相比，SCCHN 患者循环中 EGFR853 – 861 特异性 CTL 升高。因此，一种新的、免疫原性的 EGFR 编码的 CTL 表位可以被纳入疫苗中，并且可用于癌症患者中与 EGFR 特异性单克隆抗体的组合免疫治疗。
Therapeutic targeting of the epidermal growth factor receptor (EGFR), which is highly overexpressed and correlated with poor prognosis in colorectal and head and neck squamous cell carcinoma (SCCHN), has shown clinical efficacy using the blocking mAbs, cetuximab or panitumumab, but only in 10% to 20% of patients. Clinical responsiveness is correlated with certain Fcγ receptor genotypes, suggesting immune activity may contribute to therapeutic efficacy. In addition, cetuximab-resistant tumor cells exhibit ubiquitination and degradation of EGFR, which would increase its processing as a tumor antigen for cytotoxic T lymphocyte (CTL) lysis. Thus, T cell-based immunotherapy might enhance the antitumor efficacy of EGFR-specific mAbs, but CTL epitopes are poorly defined. To permit combinatorial EGFR-targeted immunotherapy, we identified a novel immunogenic wild-type sequence peptide, EGFR853 – 861 and modified its anchor sequence to enhance HLA-A*0201 binding and stimulation of cross-reactive anti-wild–type EGFR853 – 861-specific CTL. Cross-reactivity was also observed with HER2861 – 869. EGFR853 – 861-specific CTL recognition of SCCHN cells was increased by incubation of tumor cells with cetuximab, which led to EGFR degradation. In addition, EGFR853 – 861-specific CTLs were elevated in the circulation of SCCHN patients as compared with healthy control peripheral blood mononuclear cells. Thus, a novel, immunogenic EGFR-encoded CTL epitope may be incorporated into vaccines and would be useful for combinatorial immunotherapy with EGFR-specific mAbs in cancer patients.