Enhancing the efficacy of oncolytic virus immunotherapy using eicosapentaenoic acid in preclinical cancer models

Cancer is the second most deadly disease, accounting for approximately 10 million deaths worldwide (2020), with the World Health Organization estimating a 77% increase in cases by 2050. Immunotherapy has emerged as a breakthrough strategy in cancer treatment, with oncolytic viruses (OVs) showing promise as immunotherapeutic agents. Despite significant advances in the development of OVs, response rates in clinical trials remain limited and variable across patients and cancer types. Resistance to OV immunotherapy has been linked to the upregulation of immune evasion pathways, such as cyclooxygenase-2 (COX-2) mediated prostaglandin E2 (PGE2) signalling within the tumour microenvironment (TME). Therefore, targeting PGE2 production in conjunction with OV therapy may improve patient outcomes.
Eicosapentaenoic acid (EPA), an omega-3 polyunsaturated fatty acid that is safe and well-tolerated, has demonstrated anti-cancer and anti-inflammatory properties through multiple mechanisms, including the inhibition of PGE2 production. This study investigated whether combining EPA with OVs could enhance OV anti-cancer activity through the reduction of PGE2 production in various tumour models in vitro and in vivo.
Treatment of a panel of cancer cell lines with EPA led to a significant reduction in PGE2 production, particularly in high PGE2-producing cell lines, both in vitro and in vivo. EPA supplementation did not impair OV anti-cancer activity, either in their direct oncolytic effects or their ability to activate immune responses in peripheral blood mononuclear cells (PBMCs) or dendritic cells (DCs) in vitro. The combination of EPA and OV was more effective at controlling tumour growth when compared to vehicle or monotherapy controls in vivo. CXCL9 and arginase 1 were identified as candidate biomarkers and possible effectors of this combination strategy.
Overall, this thesis highlights the potential of combining EPA with OV immunotherapy to enhance anti-tumour responses, offering a novel approach to overcome immunosuppression and improve patient outcomes.