Macrophages mediate the anti-tumor effects of the oncolytic virus HSV1716 in mammary tumors

Kwan, A, Winder, NJ, Atkinson, E, Al-Janabi, HH, Allen, RJ, Hughes, R, Moamin, MR, Louie, R, Evans, D, Hutchinson, M, Capper, DT, Cox, K, Handley, JT, Wilshaw, A, Kim, T, Tazzyman, SJ, Srivastava, SK, Ottewell, PD, Vadakekolathu, J ORCID: https://orcid.org/0000-0002-2671-4285, Pockley, AG ORCID: https://orcid.org/0000-0001-9593-6431, Lewis, CE, Brown, JE, Danson, S, Conner, J and Muthana, M, 2020. Macrophages mediate the anti-tumor effects of the oncolytic virus HSV1716 in mammary tumors. Molecular Cancer Therapeutics. ISSN 1535-7163

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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, HSV1716 - they both host viral replication via a novel, PCNA-dependent mechanism and are reprogramed to express a less immunosuppressive phenotype.

Item Type:	Journal article
Publication Title:	Molecular Cancer Therapeutics
Creators:	Kwan, A., Winder, N.J., Atkinson, E., Al-Janabi, H.H., Allen, R.J., Hughes, R., Moamin, M.R., Louie, R., Evans, D., Hutchinson, M., Capper, D.T., Cox, K., Handley, J.T., Wilshaw, A., Kim, T., Tazzyman, S.J., Srivastava, S.K., Ottewell, P.D., Vadakekolathu, J., Pockley, A.G., Lewis, C.E., Brown, J.E., Danson, S., Conner, J. and Muthana, M.
Publisher:	American Association for Cancer Research
Date:	9 December 2020
ISSN:	1535-7163
Identifiers:	Number Type 10.1158/1535-7163.MCT-20-0748 DOI 1394844 Other
Divisions:	Schools > School of Science and Technology
Record created by:	Linda Sullivan
Date Added:	16 Dec 2020 14:20
Last Modified:	09 Dec 2021 03:00
URI:	https://irep.ntu.ac.uk/id/eprint/41885

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