TGFβ Treatment Enhances Glioblastoma Virotherapy by Inhibiting the Innate Immune Response

Abstract

Oncolytic viruses including oncolytic herpes simplex virus (oHSV) have produced provocative therapeutic responses in patients with glioblastoma (GB), 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, TGF-β, might reverse these effects and thereby potentiate oHSV efficacy. TGF-β treatment of NK cells rendered them less cytolytic against oHSV-infected GB cells and stem-like cells in vitro. Further, TGF-β treatment of NK cells, macrophages or microglia increased viral titers of oHSV in co-cultures with GB cells. In a syngeneic mouse model of GB, administering TGF-β prior to oHSV injection inhibited intracranial infiltration and activation of NK cells and macrophages. Notably, a single administration of TGF-β prior to oHSV therapy was sufficient to phenocopy NK cell depletion and suppress tumor growth and prolong survival in both orthograft and syngeneic models of GB. Collectively, our findings show how administering a single dose of TGF-β prior to oncolytic virus treatment of GB can transiently inhibit innate immune cells that limit efficacy, thereby improving therapeutic responses and survival outcomes.

TGF-β Inhibition Improves Oncolytic Herpes Viroimmunotherapy in Murine Models of Rhabdomyosarcoma

“…Although the combination of these agents ultimately proved to be beneficial in our mRMS survival studies, the case for TGF-β inhibition in oncolytic virotherapy is presently somewhat controversial. In a recent report by Han and colleagues, 30 TGF-β inhibition was shown to have a negative impact on oHSV treatment of a syngeneic mouse model glioblastoma because it reduced viral titers and overall survival times. Instead, mice that were given a single orthotopic injection of exogenous TGF-β1 prior to oHSV administration fared better than all other experimental groups, an observation the authors attributed to the attenuated abilities of natural killer cells and macrophages/microglia to clear oHSV-infected glioblastoma cells 30 .…”

“…In a recent report by Han and colleagues, 30 TGF-β inhibition was shown to have a negative impact on oHSV treatment of a syngeneic mouse model glioblastoma because it reduced viral titers and overall survival times. Instead, mice that were given a single orthotopic injection of exogenous TGF-β1 prior to oHSV administration fared better than all other experimental groups, an observation the authors attributed to the attenuated abilities of natural killer cells and macrophages/microglia to clear oHSV-infected glioblastoma cells 30 . Although we did not examine the functionality of innate immune cells in our tumor models following TGF-β inhibition, it seems reasonable that the de-repression of their activities could be responsible for the decreased titers of HSV1716 we obtained from tumors co-treated with A8301, especially as the early time points when these samples were collected would likely preclude the induction of an anti-virus T cell response (Figure 3C).…”

Blockade of transforming growth factor‐β signaling enhances oncolytic herpes simplex virus efficacy in patient‐derived recurrent glioblastoma models

“…53 Han et al reported that pretreatment of animals with TGF-b augmented the therapeutic effects of oHSV in both xenograft (human GBM) and syngeneic GBM models in vivo, phenocopying the outcomes of innate immune NK cell depletion. 54 On the other hand, Ilkow et al demonstrated that TGF-b produced by tumor cells reprogrammed nearby cancer-associated fibroblasts and rendered them sensitive to oncolytic rhabdovirus infection, leading to enhanced overall virus replication. 55 Thus, GBM-produced TGF-b acts on different cell types and impacts the complex cellular cross-talk between GBM and stromal/immune cells within the tumor microenvironment, which likely affects oncolytic virus activity.…”

Oncolytic herpes simplex virus interactions with the host immune system

“…Identification of the ligands could provide a target to enhance anti-tumor activity. TGF-β, an immunosuppressive cytokine, has been shown reverse NK cell and macrophage mediated inhibition of oHSV replication in glioblastoma cells in vitro and to improve oHSV efficacy in vivo [39*]. Transgenic mice expressing dominant negative TGF-β receptor in CD11c innate cells, but not CD4 + T-cells, had reduced virus replication in the eye, while expression in CD4 + T-cells resulted in reduced leukocyte infiltration [40].…”