T-independent response mediated by oncolytic tanapoxvirus recombinants expressing interleukin-2 and monocyte chemoattractant protein-1 suppresses human triple negative breast tumors

Abstract

Human triple negative breast cancer (TNBC) is an aggressive disease, associated with a high rate of recurrence and metastasis. Current therapeutics for TNBC are limited, highly toxic and show inconsistent efficacy due to a high degree of intra-tumoral and inter-tumoral heterogeneity. Oncolytic viruses (OVs) are an emerging treatment option for cancers. Several OVs are currently under investigation in preclinical and clinical settings. Here, we examine the oncolytic potential of two tanapoxvirus (TPV) recombinants expressing mouse monocyte chemoattractant protein (mMCP)-1 [also known as mCCL2] and mouse interleukin (mIL)-2, in human TNBC, in vitro and in vivo. Both wild-type (wt) TPV and TPV recombinants demonstrated efficient replicability in human TNBC cells and killed cancer cell efficiently in a dose-dependent manner in vitro. TPV/∆66R/mCCL2 and TPV/∆66R/mIL-2 expressing mCCL2 and mIL-2, respectively, suppressed the growth of MDA-MB-231 tumor xenografts in nude mice significantly, as compared to the mock-injected tumors. Histological analysis of tumors showed areas of viable tumor cells, necrotic foci and immune cell accumulation in virus-treated tumors. Moreover, TPV/∆66R/mIL-2-treated tumors showed a deep infiltration of mononuclear immune cells into the tumor capsule and focal cell death in tumors. In conclusion, TPV recombinants expressing mCCL2 and mIL-2 showed a significant therapeutic effect in MDA-MB-231 tumor xenografts, in nude mice through induction of potent antitumor immune responses. Considering the oncolytic potency of armed oncolytic TPV recombinants expressing mCCL2 and mIL-2 in an experimental nude mouse model, these viruses merit further investigation as alternative treatment options for human breast cancer.

Keywords: Antitumor macrophages; Interleukin-2; Monocyte chemoattractant protein-1/CCL2; Oncolytic virus; Tanapoxvirus; Triple negative breast cancer.