TY - JOUR
T1 - Cord blood natural killer cells expressing a dominant negative TGF-β receptor
T2 - Implications for adoptive immunotherapy for glioblastoma
AU - Yvon, Eric S.
AU - Burga, Rachel
AU - Powell, Allison
AU - Cruz, Conrad R.
AU - Fernandes, Rohan
AU - Barese, Cecilia
AU - Nguyen, Tuongvan
AU - Abdel-Baki, Mohamed S.
AU - Bollard, Catherine M.
N1 - Funding Information:
The work was supported by the Department of Defense grant CA140114 and the Alex's Lemonade Stand Foundation ‘A' Award. E.S. Yvon, C. Barese, T. Nguyen and M.S. Abdel-Baki designed and did the experiments. E.S. Yvon, C.R. Cruz and C.M. Bollard designed the research and analyzed the data. E.S. Yvon and C.M. Bollard wrote the manuscript.
Publisher Copyright:
© 2017 International Society for Cellular Therapy
PY - 2017/3/1
Y1 - 2017/3/1
N2 - 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.
AB - 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.
KW - TGF-β
KW - cord blood natural killer cells
KW - dominant negative receptor
KW - glioma
KW - immunotherapy
UR - http://www.scopus.com/inward/record.url?scp=85009775759&partnerID=8YFLogxK
U2 - 10.1016/j.jcyt.2016.12.005
DO - 10.1016/j.jcyt.2016.12.005
M3 - Article
C2 - 28109751
AN - SCOPUS:85009775759
SN - 1465-3249
VL - 19
SP - 408
EP - 418
JO - Cytotherapy
JF - Cytotherapy
IS - 3
ER -