Macrophages Mediate the Antitumor Effects of the Oncolytic Virus HSV1716 in Mammary Tumors

Abstract

Oncolytic viruses (OV) have been shown to activate the anti-tumor functions of specific immune cells like T cells. Here, we show OV can also reprogram TAMs to a less immunosuppressive phenotype. Syngeneic, immunocompetent mouse models of primary breast cancer were established using PyMT-TS1, 4T1 and E0771 cell lines and a metastatic model of breast cancer was established using the 4T1 cell line. Tumor growth and overall survival was assessed following intravenous administration of the OV, HSV1716 (a modified herpes simplex virus). Infiltration and function of various immune effector cells was assessed by NanoString, flow cytometry of dispersed tumors and immunofluorescence analysis of tumor sections. HSV1716 administration led to marked tumor shrinkage in primary mammary tumors and a decrease in metastases. This was associated with a significant increase in the recruitment/activation of cytotoxic T cells, a reduction in the presence of regulatory T cells and the reprograming of TAMs towards a pro-inflammatory, less immunosuppressive phenotype. These findings were supported by in vitro data demonstrating that human monocyte-derived macrophages (MDMs) host HSV1716 replication, and that this led to immunogenic macrophage lysis. These events were dependent on macrophage expression of proliferating cell nuclear antigen (PCNA). Finally, the anti-tumor effect of OV was markedly diminished when TAMs were depleted using clodronate liposomes. Together, our results show that TAMs play an essential role in support of the tumoricidal effect of the OV, HSV1716they both host viral replication via a novel, PCNA-dependent mechanism and are reprogramed to express a less immunosuppressive phenotype.

The Multifaceted Role of Macrophages in Oncolytic Virotherapy

“…Valproic acid, an FDA-approved anti-epileptic agent with histone deacetylase inhibitory function, is also in development for treating cancer and prevents the transcriptional activity of IFN-stimulated genes [ 91 ]. Furthermore, while commonly applied clodronate liposomes non-specifically deplete macrophages, also disabling their indirect anti-cancer activity [ 111 ], a novel, more selective agent could, for instance, interfere with systemic macrophage function or characteristic phagocytosis pathways in receptor-mediated viral clearance. However, insights suggest an important role for macrophages as cellular carriers of OVs and indicate that initial restriction of systemic macrophage functions may also have unpredicted negative effects on therapeutic outcomes.…”

“…It has been demonstrated that tumour-resident macrophages increase in number and gain more M1 characteristics upon treatment with OVs in divergent mouse models, including oncolytic adenovirus in orthotopic GBM models [ 43 , 109 ] and anaplastic thyroid carcinoma xenograft models [ 110 ], as well as oncolytic HSV-1 in athymic and syngeneic models for GBM, breast cancer, and melanoma [ 57 , 97 , 111 , 112 , 113 ]. Moreover, tumour cell death mediated by the oncolytic mumps and measles paramyxoviruses was shown to be affected by monocyte-derived macrophage responses in murine breast cancer models irrespective of the polarisation state of the initial TAM population [ 114 ].…”

Cross Talk of Macrophages with Tumor Microenvironment Cells and Modulation of Macrophages in Cancer by Virotherapy

“…In syngeneic, immunocompetent mouse models of primary breast cancer, the OV HSV1716, a modified HSV, reprogrammed TAMs toward a pro-inflammatory and perivascular phenotype, decreasing the prevalence of "tumor promoting" perivascular macrophages. Moreover, HSV1716 significantly increased the number of F4/80 TAM expressing proinflammatory, M1-like markers, IL-12 and iNOS, and reduced the expression of the M2-like marker MRC1 [52].…”

In Situ Cancer Vaccination and Immunovirotherapy Using Oncolytic HSV

“…HSV1716 inhibited mouse intracranial Harding–Passey melanoma, with HSV staining 7 days post-injection restricted to the tumors [ 38 ]. In mouse orthotopic breast cancer models HSV1716 inhibited tumor growth and metastases after intravenous administration, which was associated with increased activated CD8 + T cells, decreased Tregs, and the reprogramming of tumor-associated macrophages (TAMs) to a pro-inflammatory M1-like phenotype [ 45 ]. It was the first oHSV to enter clinical trials in Europe in a phase I trial for patients with recurrent glioma [ 92 ].…”