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Oncolytic Virotherapy Blockade by Microglia and Macrophages Requires STAT1/3 Zahid M

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Published OnlineFirst November 8, 2017; DOI: 10.1158/0008-5472.CAN-17-0599 Cancer Translational Science Research Oncolytic Virotherapy Blockade by Microglia and Macrophages Requires STAT1/3 Zahid M. Delwar1,2,3, Yvonne Kuo1, Yan H. Wen1,4, Paul S. Rennie3, and William Jia1,2 Abstract The first oncolytic virotherapy employing HSV-1 (oHSV-1) STAT1/3 was determined to be responsible for suppressing was approved recently by the FDA to treat cancer, but further oHSV-1 replication in macrophages/microglia. Treatment improvements in efficacy are needed to eradicate challenging with the oxindole/imidazole derivative C16 rescued oHSV-1 refractory tumors, such as glioblastomas (GBM). Microglia/ replication in microglia/macrophages by inhibiting STAT1/3 macrophages comprising approximately 40% of a GBM tumor activity. In the U87 xenograft model of GBM, C16 treatment may limit virotherapeutic efficacy. Here, we show these cells overcame the microglia/macrophage barrier, thereby facilitat- suppress oHSV-1 growth in gliomas by internalizing the virus ing tumor regression without causing a spread of the virus to through phagocytosis. Internalized virus remained capable of normal organs. Collectively, our results suggest a strategy to expressing reporter genes while viral replication was blocked. relieve a STAT1/3-dependent therapeutic barrier and enhance Macrophage/microglia formed a nonpermissive OV barrier, oHSV-1 oncolytic activity in GBM. preventing dissemination of oHSV-1 in the glioma mass. The Significance: These findings suggest a strategy to enhance the deficiency in viral replication in microglial cells was associated therapeutic efficacy of oncolytic virotherapy in glioblastoma. with silencing of particular viral genes. Phosphorylation of Cancer Res; 78(3); 718–30. Ó2017 AACR. Introduction neurovirulent g34.5 or both (9–12). Despite their excellent safety profile, the clinical efficacy of many oHSV-1s has been disap- Oncolytic viruses (OV) have been used as a therapeutic arsenal pointing (13, 14). for specifically destroying cancer cells through oncolysis, a killing Among many possible factors, one important reason for this mechanism characterized by cancer cell lysis through the course of lack of efficacy can be attributed to heterogeneity among tumors. lytic virus replication (1). In addition to direct cell killing by the Clinically, the tumor bed has been observed to be highly hetero- virus, it has been demonstrated that a virally induced immune genetic at the cellular level, and a significant portion of cells in response plays a pivotal role in OV therapy (2). As OVs can kill tumor mass is nontumorous (15), which, by OV standards, makes cancer cells via a mechanism distinct from the killing effects of them resistant to OV replication. We termed these cells tumor- conventional chemotherapy and radiotherapy, these viruses may associated nonpermissive (TANP) cells. be ideal for treating cancers that are nonresponsive to conven- Microglia/macrophages are important innate immune cells tional treatment. Among the various OVs, those that are herpes in GBM and many other non-CNS tumors. They are probably simplex virus type I based are the furthest advanced. A herpes the most common nontumor cells among all types of cellular virus–based OV (T-Vec) was recently approved by the FDA for the infiltrates (15–18), comprising around 40% (range, 5%–78%) treatment of melanoma after a successful completion of clinical of the content of the total tumor mass (19, 20) for glioma. trials in North America (3, 4). Badie and Schartner have further verifiedthesourceof Glioblastoma multiforme (GBM) is a treatment-refractory microglia/macrophages in a rodent GBM model. They showed brain tumor with a poor prognosis (5). The most intensely that microglia/macrophages contribute up to 46% of the investigated oncolytic HSV-1 (oHSV-1) viruses for treating GBM cellular mass of a rodent GBM tumor, with up to 34% origi- are mutant HSV-1s with deletions in viral gene ICP6 (6–8) or À þ nating from microglia (CD45 /CD11b cells) present in the brain since embryonic development and the remaining 12% 1Centre for Brain Health, University of British Columbia, Vancouver, Canada. originating from blood-derived macrophages (identified as þ þ 2Department of Surgery, University of British Columbia, Vancouver, Canada. CD45 /CD11b cells; ref. 21). 3 Department of Urologic Sciences, University of British Columbia, Vancouver, Tumor-associated microglia/macrophages play an important 4 Canada. Department of Ophthalmology, University of British Columbia, role in tumor progression (15–17, 22). There is a positive corre- Vancouver, Canada. lation between the number of microglia/macrophages and the Note: Supplementary data for this article are available at Cancer Research malignancy of the brain tumor. Malignant gliomas, such as Online (http://cancerres.aacrjournals.org/). glioblastomas and anaplastic gliomas, showed the largest number Corresponding Author: William Jia, Department of Surgery, University of British of mixed cell populations containing microglia/macrophages, Columbia, 2211 Wesbrook Mall, Vancouver, British Columbia V6T2B5, Canada. and low malignancy glial tumors contain fewer microglial cells Phone: 604-822-0728; Fax: 604-822-0361; E-mail: [email protected] (18). Regardless of the origin of macrophages in the tumor doi: 10.1158/0008-5472.CAN-17-0599 microenvironment, a large body of work has suggested that tumor Ó2017 American Association for Cancer Research. cells communicate with macrophages (15). Importantly, the 718 Cancer Res; 78(3) February 1, 2018 Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst November 8, 2017; DOI: 10.1158/0008-5472.CAN-17-0599 Oncolytic Virotherapy Inhibition by Microglia/Macrophages communication has been shown to occur in both directions, in Reagents and cells that glioma cells attract macrophage infiltration, while macro- The NF-kB inhibitor, Bay-11, the imidazolo-oxindole deriv- phages promote glioma growth and metastasis (15, 17). ative C16, and the iNOS inhibitor, aminoguanidine hydrochlo- The abundant microglia/macrophages in human GBM com- ride were obtained from Santa Cruz Biotechnology, Millipore, promise the major component of TANP cells and contribute and Tocris Bioscience, respectively. U87 (human GBM) cells significantly to the poor efficacy of OVs. A previous study found and Vero (African green monkey kidney) cells were obtained that chemical ablation of microglia/macrophages subsequently from ATCC. BV2 (mouse microglia) cells were kindly provided enhances the antitumor effect of oHSV-1 in a glioma-bearing by Dr. Stephanie Booth, Department of Medical Microbiology rodent model (23). Even for some so-called "cold" tumors that and Infectious Diseases, University of Manitoba (Manitoba, do not have large number of macrophages in the tumor mass, Canada). All cells were maintained in DMEM supplemented oncolytic virotherapy often turns the tumor to "hot" with with 10% FBS and 1% antibiotics (penicillin and streptomy- significant macrophage infiltration as fast reacting innate cin). Total passages of the cells were less than 30 times, and they immune responses. Although those macrophages are probably were routinely tested for mycoplasma. However, cell lines were M1-type that are important in killing tumor cells as shown by a not authenticated in our hand. All cells were maintained at recent study (24), they are equally or more effective in clearing 37 Cin5%CO2. out the OVs to hinder the antitumor effectiveness of OV therapy. Virus replication assay As the most predominant TANP cells in GBM, a better under- G207 virus was obtained from NeuroVir Therapeutics Inc. U87 standing of this interaction is essential for the development of (5 Â 104) cells alone, or with the indicated number of microglia novel strategies for oncolytic virotherapy against GBM and other cells in coculture, were incubated overnight with culture medium solid tumors. This report addresses the mechanism and effect of (DMEM with 10% FBS and 1% antibiotics). The next day, cells – microglia/macrophages in response to oHSV-1 infected human were infected with G207 virus at a multiplicity of infection (MOI) glioblastoma and prostate cancer cells. We hypothesized that, of 1. Viruses were harvested after 2 to 4 days postinfection. After by modifying the cellular activity of tumor-associated microglia/ three freeze-thaw cycles, viruses were titrated in triplicate on Vero fi macrophages, we might enhance the ef cacy of oHSV-1 in GBM. cells by a standard plaque assay on 12-well plates. Indeed, we found that the presence of microglia/macrophages is sufficient to hinder oHSV-1 replication in glioma cells. Our findings suggest that microglia impede the dissemination of Phagocytosis assay oHSV-1 among glioma cells mainly by uptaking oHSV-1 The phagocytosis assay was performed according to the through phagocytosis. Furthermore, although oHSV-1 fails to manufacturer's protocol (Phagocytosis Assay Kit, Cayman fl replicate in microglia/macrophages, some transgenes carried by Chemical). Brie y, microglia cells in wells of a 24-well plate the virus can still be expressed. We further found that phos- were infected with G207 or vehicle at an MOI of 1, and a 10% phorylation of STAT-1 and 3 are critical for inhibition of viral latex bead-rabbit IgG-FITC solution was added to each well. At replication in microglia/macrophages. We then discovered that 1 hour postinfection, cells were washed three times with PBS. C16, an oxindole/imidazole
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