Resistance Mechanisms Influencing Oncolytic Virotherapy, a Systematic Analysis

Abstract

Resistance to therapy is a frequently observed phenomenon in the treatment of cancer, and as with other cancer therapeutics, therapies based on oncolytic viruses also face the challenges of resistance, such as humoral and cellular antiviral responses, and tumor-associated interferon-mediated resistance. In order to identify additional mechanisms of resistance that may contribute to therapeutic failure, we developed a systematic search strategy for studies published in PubMed. We analyzed 6143 articles on oncolytic virotherapy and found that approximately 8% of these articles use resistance terms in the abstract and/or title. Of these 439 articles, 87 were original research. Most of the findings reported pertain to resistance mediated by tumor-cell-dependent interferon signaling. Yet, mechanisms such as epigenetic modifications, hypoxia-mediated inhibition, APOBEC-mediated resistance, virus entry barriers, and spatiotemporal restriction to viral spread, although not frequently assessed, were demonstrated to play a major role in resistance. Similarly, our results suggest that the stromal compartment consisting of, but not limited to, myeloid cells, fibroblasts, and epithelial cells requires more study in relation to therapy resistance using oncolytic viruses. Thus, our findings emphasize the need to assess the stromal compartment and to identify novel mechanisms that play an important role in conferring resistance to oncolytic virotherapy.

Modelling the spatial dynamics of oncolytic virotherapy in the presence of virus-resistant tumour cells

“…Potential explanations could be technical limitations related to virus delivery and treatment, variability in cancer types, generation of weak anti-tumour immunity, individual differences among patients, and occurrence of infection-resistant cancer cells [4,[8][9][10]. Here we focus on the role of resistance, as it remains to be a relatively unexplored area of research [11].…”

“…Resistance to virotherapy is a relatively unexplored area. Still, diverse mechanisms have been identified in the literature (reviewed in Bhatt et al 2021) [ 11 ], including interferon-mediated resistance, epigenetic modifications, hypoxia-mediated inhibition, APOBEC-mediated resistance, virus-entry barriers, and spatiotemporal restrictions to viral spread. In view of this diversity, we refrain from modelling a specific resistance mechanism and instead make more generic assumptions on the emergence of resistance.…”

Improving cancer immunotherapy by rationally combining oncolytic virus with modulators targeting key signaling pathways

“…One mechanism of OV therapeutic failure is tumor cell resistance to OV infection [ 297 ]. Dimethyl fumarate (DMF) is a common treatment for psoriasis and multiple sclerosis, and it also exhibits anticancer properties.…”

Cellular resistance to an oncolytic virus is driven by chronic activation of innate immunity

“…Previous work has investigated different virus resistance mechanisms. 8 These include humoral and cellular antiviral adaptive immunity after multiple doses of a given virus, 9 the activation of innate immunity pathways such as the interferon-receptor (IFNR)-based Janus-kinase (JAK-STAT) pathway, 10 epigenetic modifications, 11 , 12 , 13 hypoxia-driven inhibition of infection, 14 APOBEC-mediated viral resistance, 4 , 15 restrictions to viral binding and entry, 16 autophagy, 13 and tumor-associated spatial barriers. 17 , 18 , 19 , 20 , 21 More specifically, the activation of master regulators such as the beta subunit of nuclear factor kappa-B kinase (IKK), 22 as well as inositol polyphosphate 5-phosphatase (Inpp5e), 23 mitogen-activated protein kinase (MAPK), 24 multidrug-resistance protein-1 (MDR1), 25 mitogen-activated protein kinase kinase (MEK), 26 second mitochondria-derived activator of caspases (SMAC), 27 , 28 sirtuin 1 (SIRT1), 29 and N-myc proto-oncogene protein (MYCN), 30 have been found to be associated with resistance to viral infection and replication in tumor cells.…”