Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA, USA.
J Immunother. 2010 Jan;33(1):83-91. doi: 10.1097/CJI.0b013e3181b8f421.
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 Fcgamma 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.
表皮生长因子受体 (EGFR) 的治疗靶向，在结直肠癌和头颈部鳞状细胞癌 (SCCHN) 中高度过表达并与预后不良相关，使用阻断 mAb（西妥昔单抗或帕尼单抗）已显示出临床疗效，但仅在 10% 到 20% 的患者中有效。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增强 EGFR 特异性 mAb 的抗肿瘤疗效，但 CTL 表位尚未明确。为了允许组合式 EGFR 靶向免疫疗法，我们鉴定了一种新型免疫原性野生型序列肽，EGFR853-861，并修饰了其锚序列以增强 HLA-A*0201 结合和交叉反应性抗野生型 EGFR853-861 特异性 CTL 的刺激。还观察到与 HER2861-869 的交叉反应性。与健康对照组外周血单个核细胞相比，西妥昔单抗孵育可增加 SCCHN 细胞中 EGFR853-861 特异性 CTL 的识别，从而导致 EGFR 降解。此外，与健康对照组外周血单个核细胞相比，SCCHN 患者的循环中 EGFR853-861 特异性 CTL 升高。因此，一种新型的、免疫原性的 EGFR 编码 CTL 表位可被纳入疫苗中，并可与癌症患者的 EGFR 特异性 mAb 联合免疫治疗一起使用。
