title: Human regulatory T cells kill tumor cells through granzyme-dependent cytotoxicity upon retargeting with a bispecific antibody.
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.
authors.affiliation: 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.
authors.forename: Bryan D
authors.initials: BD
authors.lastname: Choi
authors.affiliation: 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.
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Gedeon
authors.affiliation: Department of Biostatistics and Bioinformatics, Duke University, Durham, NC 27710.
authors.forename: James E
authors.initials: JE
authors.lastname: Herndon
authors.affiliation: Duke Brain Tumor Immunotherapy Program, Division of Neurosurgery, Department of Surgery, Duke University Medical Center, Durham, NC 27710.
authors.forename: Gary E
authors.initials: GE
authors.lastname: Archer
authors.affiliation: Duke Brain Tumor Immunotherapy Program, Division of Neurosurgery, Department of Surgery, Duke University Medical Center, Durham, NC 27710.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Reap
authors.affiliation: Duke Brain Tumor Immunotherapy Program, Division of Neurosurgery, Department of Surgery, Duke University Medical Center, Durham, NC 27710.
authors.forename: Luis
authors.initials: L
authors.lastname: Sanchez-Perez
authors.affiliation: 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.
authors.forename: Duane A
authors.initials: DA
authors.lastname: Mitchell
authors.affiliation: 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.
authors.forename: Darell D
authors.initials: DD
authors.lastname: Bigner
authors.affiliation: 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.
authors.forename: John H
authors.initials: JH
authors.lastname: Sampson
mesh_terms: D018033:Antibodies, Bispecific / Q000276:immunology*; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D005909:Glioblastoma / Q000276:immunology*; D053804:Granzymes / Q000378:metabolism*; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D054353:Perforin / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D018033:Antibodies, Bispecific; D054353:Perforin; D053804:Granzymes
keywords: Bispecific Antibodies; Glioblastoma; Granzymes; Immunomodulation; Regulatory T Cells