Duke Brain Tumor Immunotherapy Program, Division of Neurosurgery, Department of Surgery, Duke University Medical Center, Durham, NC 27710 ; Department of Pathology, Duke University Medical Center, Durham, NC 27710.
Duke Brain Tumor Immunotherapy Program, Division of Neurosurgery, Department of Surgery, Duke University Medical Center, Durham, NC 27710 ; Department of Biomedical Engineering, Duke University, Durham, NC 27708.
Cancer Immunol Res. 2013 Sep;1(3):163. doi: 10.1158/2326-6066.CIR-13-0049.
A major mechanism by which human regulatory T cells (T(regs)) have been shown to suppress and kill autologous immune cells is through the granzyme-perforin pathway. However, it is unknown whether T(regs) also possess the capacity to kill tumor cells using similar mechanisms. Bispecific antibodies (bscAbs) have emerged as a promising class of therapeutics that activate T cells against tumor antigens without the need for classical MHC-restricted TCR recognition. Here, we show that a bscAb targeting the tumor-specific mutation of the epidermal growth factor receptor, EGFRvIII, redirects human CD4(+)CD25(+)FoxP3(+) T(regs) to kill glioblastoma (GBM) cells. This activity was significantly abrogated by inhibitors of the granzyme-perforin pathway. Notably, analyses of human primary GBM also displayed diffuse infiltration of granzyme-expressing FoxP3(+) T cells. Together, these data suggest that despite their known suppressive functions, tumor-infiltrating T(regs) possess potent cytotoxic mechanisms that can be co-opted for efficient tumor cell lysis.
一种主要的机制表明，人类调节性 T 细胞（Tregs）通过颗粒酶-穿孔素途径抑制和杀死自身免疫细胞。然而，目前尚不清楚 Tregs 是否也具有使用类似机制杀死肿瘤细胞的能力。双特异性抗体（bscAbs）已成为一类很有前途的治疗药物，它们可以激活针对肿瘤抗原的 T 细胞，而不需要经典的 MHC 限制性 TCR 识别。在这里，我们表明，针对表皮生长因子受体（EGFRvIII）的肿瘤特异性突变的 bscAb 可将人 CD4+CD25+FoxP3+Tregs 重定向以杀死胶质母细胞瘤（GBM）细胞。这种活性被颗粒酶-穿孔素途径的抑制剂显著阻断。值得注意的是，对人类原发性 GBM 的分析也显示出颗粒酶表达的 FoxP3+T 细胞的弥漫浸润。综上所述，这些数据表明，尽管 Tregs 具有已知的抑制功能，但浸润肿瘤的 Tregs 具有强大的细胞毒性机制，可以被有效地用于肿瘤细胞裂解。
