TY - JOUR
T1 - Bortezomib treatment sensitizes oncolytic HSV-1-treated tumors to NK cell immunotherapy
AU - Yoo, Ji Young
AU - Jaime-Ramirez, Alena Cristina
AU - Bolyard, Chelsea
AU - Dai, Hongsheng
AU - Nallanagulagari, Tejaswini
AU - Wojton, Jeffrey
AU - Hurwitz, Brian S.
AU - Relation, Theresa
AU - Lee, Tae Jin
AU - Lotze, Michael T.
AU - Yu, Jun Ge
AU - Zhang, Jianying
AU - Croce, Carlo M.
AU - Yu, Jianhua
AU - Caligiuri, Michael A.
AU - Old, Matthew
AU - Kaur, Balveen
N1 - Publisher Copyright:
© 2016 American Association for Cancer Research.
PY - 2016/11/1
Y1 - 2016/11/1
N2 - Purpose: Both the proteasome inhibitor bortezomib and an oncolytic herpes simplex virus-1 (oHSV)-expressing GM-CSF are currently FDA approved. Although proteasome blockade can increase oHSV replication, immunologic consequences, and consequent immunotherapy potential are unknown. In this study, we investigated the impact of bortezomib combined with oHSV on tumor cell death and sensitivity to natural killer (NK) cell immunotherapy. Experimental Design: Western blot, flow cytometry, and caspase 3/7 activity assays were used to evaluate the induction of apoptosis/autophagy and/or necroptotic cell death. Cellular and mitochondrial reactive oxygen species (ROS) production was measured using CellROX and MitoSOX. Inhibitors/shRNA-targeting ROS, JNK and RIP1 kinase (RIPK1) were used to investigate the mechanism of cell killing. The synergistic interaction between oHSV and bortezomib was calculated using a Chou-Talalay analysis. NK cells isolated from normal human blood were co-cultured with tumor cells to evaluate cellular interactions. Q-PCR, ELISA, and FACS analysis were used to evaluate NK cell activation. Intracranial tumor xenografts were used to evaluate antitumor efficacy. Results: Combination treatment with bortezomib- and oHSV induced necroptotic cell death and increased the production of mitochondrial ROS and JNK phosphorylation. Inhibitors/shRNA of RIPK1 and JNK rescued synergistic cell killing. Combination treatment also significantly enhanced NK cell activation and adjuvant NK cell therapy of mice treated with bortezomib and oHSV improved antitumor efficacy. Conclusions: This study provides a significant rationale for triple combination therapy with bortezomib, oHSV, and NK cells to improve efficacy, in glioblastoma patients.
AB - Purpose: Both the proteasome inhibitor bortezomib and an oncolytic herpes simplex virus-1 (oHSV)-expressing GM-CSF are currently FDA approved. Although proteasome blockade can increase oHSV replication, immunologic consequences, and consequent immunotherapy potential are unknown. In this study, we investigated the impact of bortezomib combined with oHSV on tumor cell death and sensitivity to natural killer (NK) cell immunotherapy. Experimental Design: Western blot, flow cytometry, and caspase 3/7 activity assays were used to evaluate the induction of apoptosis/autophagy and/or necroptotic cell death. Cellular and mitochondrial reactive oxygen species (ROS) production was measured using CellROX and MitoSOX. Inhibitors/shRNA-targeting ROS, JNK and RIP1 kinase (RIPK1) were used to investigate the mechanism of cell killing. The synergistic interaction between oHSV and bortezomib was calculated using a Chou-Talalay analysis. NK cells isolated from normal human blood were co-cultured with tumor cells to evaluate cellular interactions. Q-PCR, ELISA, and FACS analysis were used to evaluate NK cell activation. Intracranial tumor xenografts were used to evaluate antitumor efficacy. Results: Combination treatment with bortezomib- and oHSV induced necroptotic cell death and increased the production of mitochondrial ROS and JNK phosphorylation. Inhibitors/shRNA of RIPK1 and JNK rescued synergistic cell killing. Combination treatment also significantly enhanced NK cell activation and adjuvant NK cell therapy of mice treated with bortezomib and oHSV improved antitumor efficacy. Conclusions: This study provides a significant rationale for triple combination therapy with bortezomib, oHSV, and NK cells to improve efficacy, in glioblastoma patients.
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U2 - 10.1158/1078-0432.CCR-16-1003
DO - 10.1158/1078-0432.CCR-16-1003
M3 - Article
C2 - 27390350
AN - SCOPUS:84993987097
SN - 1078-0432
VL - 22
SP - 5265
EP - 5276
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 21
ER -