TY - JOUR
T1 - TGFβ treatment enhances glioblastoma virotherapy by inhibiting the innate immune response
AU - Han, Jianfeng
AU - Chen, Xilin
AU - Chu, Jianhong
AU - Xu, Bo
AU - Meisen, Walter H.
AU - Chen, Lichao
AU - Zhang, Lingling
AU - Zhang, Jianying
AU - He, Xiaoming
AU - Wang, Qi En
AU - Chiocca, E. Antonio
AU - Kaur, Balveen
AU - Caligiuri, Michael A.
AU - Yu, Jianhua
N1 - Publisher Copyright:
© 2015 American Association for Cancer Research.
PY - 2015/12/15
Y1 - 2015/12/15
N2 - Oncolytic viruses, including oncolytic herpes simplex virus (oHSV), have produced provocative therapeutic responses in patients with glioblastoma, the most aggressive brain tumor. Paradoxically, innate immune responses mediated by natural killer (NK) cells and macrophages/microglia appear to limit oHSV efficacy. Therefore, we investigated whether pretreatment with an immunosuppressive cytokine, TGFβ, might reverse these effects and thereby potentiate oHSV efficacy. TGFβ treatment of NK cells rendered them less cytolytic against oHSV-infected glioblastoma cells and stem-like cells in vitro. Furthermore, TGFβ treatment of NK cells, macrophages, or microglia increased viral titers of oHSV in cocultures with glioblastoma cells. In a syngeneic mouse model of glioblastoma, administering TGFβ prior to oHSV injection inhibited intracranial infiltration and activation of NK cells and macrophages. Notably, a single administration of TGFβ prior to oHSV therapy was sufficient to phenocopy NK-cell depletion and suppress tumor growth and prolong survival in both xenograft and syngeneic models of glioblastoma. Collectively, our findings show how administering a single dose of TGFβ prior to oncolytic virus treatment of glioblastoma can transiently inhibit innate immune cells that limit efficacy, thereby improving therapeutic responses and survival outcomes.
AB - Oncolytic viruses, including oncolytic herpes simplex virus (oHSV), have produced provocative therapeutic responses in patients with glioblastoma, the most aggressive brain tumor. Paradoxically, innate immune responses mediated by natural killer (NK) cells and macrophages/microglia appear to limit oHSV efficacy. Therefore, we investigated whether pretreatment with an immunosuppressive cytokine, TGFβ, might reverse these effects and thereby potentiate oHSV efficacy. TGFβ treatment of NK cells rendered them less cytolytic against oHSV-infected glioblastoma cells and stem-like cells in vitro. Furthermore, TGFβ treatment of NK cells, macrophages, or microglia increased viral titers of oHSV in cocultures with glioblastoma cells. In a syngeneic mouse model of glioblastoma, administering TGFβ prior to oHSV injection inhibited intracranial infiltration and activation of NK cells and macrophages. Notably, a single administration of TGFβ prior to oHSV therapy was sufficient to phenocopy NK-cell depletion and suppress tumor growth and prolong survival in both xenograft and syngeneic models of glioblastoma. Collectively, our findings show how administering a single dose of TGFβ prior to oncolytic virus treatment of glioblastoma can transiently inhibit innate immune cells that limit efficacy, thereby improving therapeutic responses and survival outcomes.
UR - http://www.scopus.com/inward/record.url?scp=84955485418&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84955485418&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-15-0894
DO - 10.1158/0008-5472.CAN-15-0894
M3 - Article
C2 - 26631269
AN - SCOPUS:84955485418
SN - 0008-5472
VL - 75
SP - 5273
EP - 5282
JO - Cancer Research
JF - Cancer Research
IS - 24
ER -