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.

Oncolytic viruses (OV) promote anti-tumour responses through the initiation of immunogenic cancer cell death which activates the host’s systemic anti-tumour immunity. We have previously shown that intravenously administered HSV1716 is an effective treatment for mammary cancer. However, intravenous administration of a virus has the potential to result in neutralization and sequestration of the virus which may reduce efficacy. Here, we show that the oncolytic virus HSV1716 can be administered within a cellular carrier (macrophages). PyMT and 4T1 murine mammary cancer cell lines were implanted into immuno-competent murine models (orthotopic primary, early metastatic and brain metastasis models). HSV1716 or macrophages armed with HSV1716 (M-HSV1716) were administered intravenously, and tumour size was quantified using caliper measurement or bioluminescence imaging. Administration of M-HSV1716 led to tumour shrinkage and increased the survival of animals. Furthermore, these results were achieved with a 100-fold lower viral load, which has the potential for decreased toxicity. Our results demonstrate that M-HSV1716 is associated with activity against murine mammary cancers and provides an alternative platform for the systemic delivery of OV.

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<p>Supplementary Tables and Figures</p>

<p>Supplementary Tables and Figures</p>