PMID- 24570975
OWN - NLM
STAT- MEDLINE
DCOM- 20150724
LR  - 20211021
IS  - 2326-6074 (Electronic)
IS  - 2326-6066 (Print)
IS  - 2326-6066 (Linking)
VI  - 1
IP  - 3
DP  - 2013 Sep
TI  - Human regulatory T cells kill tumor cells through granzyme-dependent cytotoxicity 
      upon retargeting with a bispecific antibody.
PG  - 163
LID - 10.1158/2326-6066.CIR-13-0049 [doi]
AB  - 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.
FAU - Choi, Bryan D
AU  - Choi BD
AD  - 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.
FAU - Gedeon, Patrick C
AU  - Gedeon PC
AD  - 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.
FAU - Herndon, James E 2nd
AU  - Herndon JE 2nd
AD  - Department of Biostatistics and Bioinformatics, Duke University, Durham, NC 
      27710.
FAU - Archer, Gary E
AU  - Archer GE
AD  - Duke Brain Tumor Immunotherapy Program, Division of Neurosurgery, Department of 
      Surgery, Duke University Medical Center, Durham, NC 27710.
FAU - Reap, Elizabeth A
AU  - Reap EA
AD  - Duke Brain Tumor Immunotherapy Program, Division of Neurosurgery, Department of 
      Surgery, Duke University Medical Center, Durham, NC 27710.
FAU - Sanchez-Perez, Luis
AU  - Sanchez-Perez L
AD  - Duke Brain Tumor Immunotherapy Program, Division of Neurosurgery, Department of 
      Surgery, Duke University Medical Center, Durham, NC 27710.
FAU - Mitchell, Duane A
AU  - Mitchell DA
AD  - 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.
FAU - Bigner, Darell D
AU  - Bigner DD
AD  - 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.
FAU - Sampson, John H
AU  - Sampson JH
AD  - 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.
LA  - eng
GR  - 5P50-NS020023- 29/NS/NINDS NIH HHS/United States
GR  - P50 NS020023/NS/NINDS NIH HHS/United States
GR  - R01 CA135272/CA/NCI NIH HHS/United States
GR  - F30 CA177152/CA/NCI NIH HHS/United States
GR  - 3R25-NS065731-03S1/NS/NINDS NIH HHS/United States
GR  - NIH 5R01-CA135272-04/CA/NCI NIH HHS/United States
GR  - T32 GM007171/GM/NIGMS NIH HHS/United States
GR  - 1F30CA177152-01/CA/NCI NIH HHS/United States
GR  - R25 NS065731/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Cancer Immunol Res
JT  - Cancer immunology research
JID - 101614637
RN  - 0 (Antibodies, Bispecific)
RN  - 126465-35-8 (Perforin)
RN  - EC 3.4.21.- (Granzymes)
SB  - IM
MH  - Antibodies, Bispecific/*immunology
MH  - Cell Line, Tumor
MH  - *Cytotoxicity, Immunologic
MH  - Glioblastoma/*immunology
MH  - Granzymes/*metabolism
MH  - Humans
MH  - Lymphocyte Activation/immunology
MH  - Perforin/*metabolism
MH  - T-Lymphocytes, Regulatory/*immunology
PMC - PMC3932050
MID - NIHMS525715
OTO - NOTNLM
OT  - Bispecific Antibodies
OT  - Glioblastoma
OT  - Granzymes
OT  - Immunomodulation
OT  - Regulatory T Cells
COIS- Conflict of Interest Statement: The authors B.D.C., D.D.B. and J.H.S. have a 
      patent pending for EGFRvIII as a tumor-specific target for bispecific antibody 
      therapy.
EDAT- 2014/02/27 06:00
MHDA- 2015/07/25 06:00
PMCR- 2014/09/01
CRDT- 2014/02/27 06:00
PHST- 2014/02/27 06:00 [entrez]
PHST- 2014/02/27 06:00 [pubmed]
PHST- 2015/07/25 06:00 [medline]
PHST- 2014/09/01 00:00 [pmc-release]
AID - 10.1158/2326-6066.CIR-13-0049 [doi]
PST - ppublish
SO  - Cancer Immunol Res. 2013 Sep;1(3):163. doi: 10.1158/2326-6066.CIR-13-0049.