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Cancer Immunol Res. 2013 Sep;1(3):163. doi: 10.1158/2326-6066.CIR-13-0049.

Human regulatory T cells kill tumor cells through granzyme-dependent cytotoxicity upon retargeting with a bispecific antibody.

Author information

1
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.
2
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.
3
Department of Biostatistics and Bioinformatics, Duke University, Durham, NC 27710.
4
Duke Brain Tumor Immunotherapy Program, Division of Neurosurgery, Department of Surgery, Duke University Medical Center, Durham, NC 27710.
5
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 ; The Preston Robert Tisch Brain Tumor Center at Duke, Duke University Medical Center, Durham, NC 27710.
6
Department of Pathology, Duke University Medical Center, Durham, NC 27710 ; The Preston Robert Tisch Brain Tumor Center at Duke, Duke University Medical Center, Durham, NC 27710.

Abstract

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.

KEYWORDS:

Bispecific Antibodies; Glioblastoma; Granzymes; Immunomodulation; Regulatory T Cells

PMID:
24570975
PMCID:
PMC3932050
DOI:
10.1158/2326-6066.CIR-13-0049
[Indexed for MEDLINE]
Free PMC Article

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