title: Cord blood natural killer cells expressing a dominant negative TGF-β receptor: Implications for adoptive immunotherapy for glioblastoma.
abstract: Cord blood (CB) natural killer (NK) cells are promising effector cells for tumor immunotherapy but are currently limited by immune-suppressive cytokines in the tumor microenvironment, such as transforming growth factor (TGF-β). We observed that TGF-β inhibits expression of activating receptors such as NKG2D and DNAM1 and decreases killing activity against glioblastoma tumor cells through inhibition of perforin secretion. To overcome the detrimental effects of TGF-β, we engrafted a dominant negative TGF-β receptor II (DNRII) on CB-derived NK cells by retroviral transduction and evaluated their ability to kill glioblastoma cells in the presence of TGF-β. After manufacture using Good Manufacturing Practice-compliant methodologies and transduction with DNRII, CB-derived DNRII-transduced NK cells expanded to clinically relevant numbers and retained both their killing ability and their secretion of interferon-γ upon activation. More important, these cells maintained both perforin expression and NKG2D/DNMA1 expression in the presence of TGF-β allowing for recognition and killing of glioblastoma tumor cells. Hence, NK cells expressing a DNRII should have a functional advantage over unmodified NK cells in the presence of TGF-β-secreting tumors and may be an important therapeutic approach for patients with cancer.
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, The University of Texas, Houston, Texas.
authors.forename: Eric S
authors.initials: ES
authors.lastname: Yvon
authors.affiliation: Institute for Biomedical Sciences, The George Washington University, Washington, DC, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Burga
authors.affiliation: Institute for Biomedical Sciences, The George Washington University, Washington, DC, USA.
authors.forename: Allison
authors.initials: A
authors.lastname: Powell
authors.affiliation: Institute for Biomedical Sciences, The George Washington University, Washington, DC, USA.
authors.forename: Conrad R
authors.initials: CR
authors.lastname: Cruz
authors.affiliation: Institute for Biomedical Sciences, The George Washington University, Washington, DC, USA.
authors.forename: Rohan
authors.initials: R
authors.lastname: Fernandes
authors.affiliation: Institute for Biomedical Sciences, The George Washington University, Washington, DC, USA.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Barese
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, The University of Texas, Houston, Texas.
authors.forename: Tuongvan
authors.initials: T
authors.lastname: Nguyen
authors.affiliation: Nationwide Children's Hospital, Columbus, Ohio.
authors.forename: Mohamed S
authors.initials: MS
authors.lastname: Abdel-Baki
authors.affiliation: Institute for Biomedical Sciences, The George Washington University, Washington, DC, USA. Electronic address: cbollard@cnmc.org.
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Bollard
mesh_terms: D001932:Brain Neoplasms / Q000276:immunology / Q000628:therapy*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D005312:Fetal Blood / Q000166:cytology* / Q000276:immunology / Q000637:transplantation; D005799:Genes, Dominant; D015316:Genetic Therapy / Q000379:methods*; D005909:Glioblastoma / Q000276:immunology / Q000628:therapy*; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007371:Interferon-gamma / Q000378:metabolism; D019169:Jurkat Cells; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000166:cytology / Q000378:metabolism / Q000637:transplantation*; D054353:Perforin / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D016207:Cytokines; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D054353:Perforin; D007371:Interferon-gamma; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II
keywords: TGF-β; cord blood natural killer cells; dominant negative receptor; glioma; immunotherapy