BAI1 Orchestrates Macrophage Inflammatory Response to HSV Infection—Implications for Oncolytic Viral Therapy

Abstract

Purpose Brain Angiogenesis Inhibitor (BAI1) facilitates phagocytosis, and bacterial pathogen clearance by macrophages; however, its role in viral infections is unknown. Here we examined the role of BAI1, and its N-terminal cleavage fragment (Vstat120) in antiviral macrophage responses to oncolytic herpes simplex virus (oHSV). Experimental Design Changes in infiltration and activation of monocytic and microglial cells after treatment of glioma-bearing mice brains with a control (rHSVQ1) or Vstat120-expressing (RAMBO) oHSV was analyzed using flow cytometry. Co-culture of infected glioma cells with macrophages or microglia was used to examine antiviral signaling. Cytokine array gene expression and ingenuity pathway analysis (IPA) helped evaluate changes in macrophage signaling in response to viral infection. TNFα blocking antibodies and macrophages derived from Bai1−/− mice were used. Results RAMBO treatment of mice reduced recruitment and activation of macrophages/microglia in mice with brain tumors, and showed increased virus replication compared to rHSVQ1. Cytokine gene expression array revealed that RAMBO significantly altered the macrophage inflammatory response to infected glioma cells via altered secretion of TNFα. Further we showed that BAI1 mediated macrophage TNFα induction in response to oHSV therapy. Intracranial inoculation of wild type/RAMBO virus in Bai1−/− or wild type non-tumor-bearing mice revealed the safety of this approach. Conclusions We have uncovered a new role for BAI1 in facilitating macrophage anti-viral responses. We show that arming oHSV with antiangiogenic Vstat120 also shields them from inflammatory macrophage antiviral response, without reducing safety.

Myelolytic Treatments Enhance Oncolytic Herpes Virotherapy in Models of Ewing Sarcoma by Modulating the Immune Microenvironment

“…When we depleted macrophages with Clodrosome prior to rRp450 injection, however, we found that the majority of A673 xenografts shrank to CR (8/14 CR). Although we hypothesized that the improved antitumor efficacy of oncolytic virus with macrophage depletion was likely due to increased virus production and/or spread, given that macrophages are known to phagocytose virus-infected cells, 14 , 25 we did not observe a significant impact of macrophage depletion on rRp450 replication kinetics in A673 xenografts except after 144 hr, at which time the amount of virus recovered from tumors was even less in the Clodrosome group ( Figure 1 C). These data suggest that tumor macrophages diminish the effects of virotherapy through mechanisms other than inhibiting oncolysis.…”

Lifting the innate immune barriers to antitumor immunity

“…Another PtdSer receptor BAI1 has been shown to drive a proinflammatory anti-gram-negative bacterial macrophage response against Salmonella enterica serotype typhimurium, 170 as well as an antiviral macrophage response against oncolytic herpes simplex virus. 171 Whether BAI1-dependent efferocytosis has any role in tumor progression remains unknown. While macrophages are considered the major undertakers and therefore the effectors of PtdSerdirected interventions, it was described that treatment of mouse melanoma models by a combination of anti-PtdSer antibody and anti-PD-1 resulted in reduction of MDSCs and enhancement of antitumor immune response.…”

Complex role of NK cells in regulation of oncolytic virus–bortezomib therapy

“…by flow cytometry using a fluorescence-activated cell sorter (LSRII; Becton-Dickinson), and data were analyzed by using FloJo software as described (5,43).…”