Modulating Lipid Flux Sensitizes Tumours in a Fatty Tumour Microenvironment to Oncolytic Virus Therapy

Abstract

The tumour microenvironment (TME) is an important determinant of successful drug intervention. In ‘fatty’ tumours such as breast cancer, adipocytes are abundant and active in the TME. Ovarian cancers demonstrate an overwhelming metastasis to the omentum (a site of abdominal fat storage), indicating a propensity for a fat rich TME. Adipocytes are well known for their rich source of energy and endocrine function but there is a growing body of evidence for a role in driving resistance to anti-cancer therapies across a diverse range of treatment modalities. Oncolytic viruses (OVs) are a unique class of immunotherapeutic drugs that selectively lyse cancer cells and initiate a host anti-tumour immune response. We sought to determine the effects of adipose tissue and adipocyte-secreted factors on responses to OV therapy. Here, we found that tumours in a fat rich TME in vivo or receiving adipocyte-secreted factors in vitro are strongly resistant to OV infection. By employing a protease or using lipid-depletion strategies, we determined that the inhibitory effect derives from lipid constituents in adipocyte conditioned media (ACM). Closer examination of cells receiving ACM revealed that cancer cells become strikingly accumulated with lipids and this coincides with a metabolic shift favouring lipid metabolism. In an effort to overcome adipocyte mediated OV resistance, we briefly evaluated the effect of limiting de novo lipogenesis and, more extensively, blocking fatty acid (FA) uptake by FA transport proteins (FATPs). We found that blocking FA uptake, specifically FATP2-mediated FA transport, can mitigate the OV inhibitory effects of adipocyte secreted factors in vitro and in vivo, in our models. The findings from this thesis highlight the therapeutic advantage of incorporating lipid modulating strategies in combinatorial approaches with OVs.