Department of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
Department of Pathology and Laboratory Medicine; University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
Cancer Immunol Res. 2015 May;3(5):455-63. doi: 10.1158/2326-6066.CIR-14-0208. Epub 2015 Mar 19.
Vaccination strategies incorporating the immunodominant HLA-A2-restricted HER2/neu-derived peptide 369-377 (HER2369-377) are increasingly utilized in HER2/neu-expressing cancer patients. The failure of postvaccination HER2369-377-specific CD8(+) T cells to recognize HLA-A2(pos)HER2/neu-expressing cells in vitro, however, has been attributed to impaired MHC class I/HLA-A2 presentation observed in HER2/neu-overexpressing tumors. We reconcile this controversy by demonstrating that HER2369-377 is directly recognized by high functional-avidity HER2369-377-specific CD8(+) T cells-either genetically modified to express a novel HER2369-377 TCR or sensitized using HER2369-377-pulsed type 1-polarized dendritic cells (DC1)-on class I-abundant HER2(low), but not class I-deficient HER2(high), cancer cells. Importantly, a critical cooperation between CD4(+) T-helper type-1 (Th1) cytokines IFNγ/TNFα and HER2/neu-targeted antibody trastuzumab is necessary to restore class I expression in HER2(high) cancers, thereby facilitating recognition and lysis of these cells by HER2369-377-specific CD8(+) T cells. Concomitant induction of PD-L1 on HER2/neu-expressing cells by IFNγ/TNF and trastuzumab, however, has minimal impact on DC1-sensitized HER2369-377-CD8(+) T-cell-mediated cytotoxicity. Although activation of EGFR and HER3 signaling significantly abrogates IFNγ/TNFα and trastuzumab-induced class I restoration, EGFR/HER3 receptor blockade rescues class I expression and ensuing HER2369-377-CD8(+) cytotoxicity of HER2/neu-expressing cells. Thus, combinations of CD4(+) Th1 immune interventions and multivalent targeting of HER family members may be required for optimal anti-HER2/neu CD8(+) T-cell-directed immunotherapy.
包含免疫优势 HLA-A2 限制的 HER2/neu 衍生肽 369-377（HER2369-377）的疫苗接种策略越来越多地用于 HER2/neu 表达的癌症患者。然而，接种疫苗后，HER2369-377 特异性 CD8+T 细胞无法在体外识别 HLA-A2（+）HER2/neu 表达的细胞，这归因于在 HER2/neu 过表达的肿瘤中观察到的 MHC 类 I/HLA-A2 呈递受损。我们通过证明 HER2369-377 直接被高功能亲和力的 HER2369-377 特异性 CD8+T 细胞识别来解决这一争议-通过表达新型 HER2369-377 TCR 的基因修饰或使用 HER2369-377 脉冲的 1 型极化树突状细胞（DC1）致敏-在 I 类丰富的 HER2（低），但不是 I 类缺乏的 HER2（高），癌细胞。重要的是，CD4+T 辅助型 1（Th1）细胞因子 IFNγ/TNFα 和 HER2/neu 靶向抗体曲妥珠单抗之间的关键合作对于恢复 HER2（高）癌症中的 I 类表达是必要的，从而促进这些细胞被 HER2369-377 特异性 CD8+T 细胞识别和裂解。然而，IFNγ/TNF 和曲妥珠单抗诱导的 PD-L1 同时在 HER2/neu 表达的细胞上表达，对 DC1 致敏的 HER2369-377-CD8+T 细胞介导的细胞毒性影响很小。虽然 EGFR 和 HER3 信号的激活显著阻断了 IFNγ/TNFα 和曲妥珠单抗诱导的 I 类恢复，但 EGFR/HER3 受体阻断可挽救 HER2/neu 表达细胞的 I 类表达和随之而来的 HER2369-377-CD8+细胞毒性。因此，CD4+Th1 免疫干预的组合和 HER 家族成员的多价靶向可能是优化抗 HER2/neu CD8+T 细胞定向免疫治疗所必需的。
