TGFβ treatment enhances glioblastoma virotherapy by inhibiting the innate immune response

Jianfeng Han, Xilin Chen, Jianhong Chu, Bo Xu, Walter H. Meisen, Lichao Chen, Lingling Zhang, Jianying Zhang, Xiaoming He, Qi En Wang, E. Antonio Chiocca, Balveen Kaur, Michael A. Caligiuri, Jianhua Yu

Research output: Contribution to journalArticlepeer-review

62 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)5273-5282
Number of pages10
JournalCancer Research
Volume75
Issue number24
DOIs
StatePublished - Dec 15 2015
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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