Human Regulatory T Cells Kill Tumor Cells through Granzyme-Dependent Cytotoxicity upon Retargeting with a Bispecific Antibody

A major mechanism by which human regulatory T cells (T-reg) 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 (bscAb) have emerged as a promising class of therapeutics that activate T cells against tumor antigens without the need for classical MHC-restricted T-cell receptor (TCR) recognition. Here, we show that a bscAb targeting the tumor-specific mutation of the EGF receptor, EGFRvIII, redirects human CD4(+)CD25(+)FoxP3(+) T-regs to kill glioblastoma cells. This activity was significantly abrogated by inhibitors of the granzyme-perforin pathway. Notably, analyses of human primary glioblastoma also displayed diffused 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. (C) 2013 AACR.