Microtubule disruption synergizes with oncolytic virotherapy by inhibiting interferon translation and potentiating bystander killing

Abstract

In this study, we show that several microtubule-destabilizing agents used for decades for treatment of cancer and other diseases also sensitize cancer cells to oncolytic rhabdoviruses and improve therapeutic outcomes in resistant murine cancer models. Drug-induced microtubule destabilization leads to superior viral spread in cancer cells by disrupting type I IFN mRNA translation, leading to decreased IFN protein expression and secretion. Furthermore, microtubule-destabilizing agents specifically promote cancer cell death following stimulation by a subset of infection-induced cytokines, thereby increasing viral bystander effects. This study reveals a previously unappreciated role for microtubule structures in the regulation of the innate cellular antiviral response and demonstrates that unexpected combinations of approved chemotherapeutics and biological agents can lead to improved therapeutic outcomes.

Recent advances in vesicular stomatitis virus-based oncolytic virotherapy: a 5-year update

“…Several microtubule-destabilizing agents (colchicine, vinorelbine, nocodazole, albendazole and parbendazole) have also been shown to sensitize 786-0 human renal carcinoma cells to oncolytic VSV [77]. Colchicine increased VSV-D M51 spread and oncolytic activity in resistant syngeneic and transgenic tumour mouse models.…”

“…Colchicine increased VSV-D M51 spread and oncolytic activity in resistant syngeneic and transgenic tumour mouse models. Interestingly, the microtubule-destabilizing agents were shown to inhibit translation of type I IFN mRNAs and enhance bystander death by virus-induced cytokines [77].…”

Selective replication of oncolytic virus M1 results in a bystander killing effect that is potentiated by Smac mimetics

“…Therefore, proteins in the UV-supernatant synergized with SMCs are likely cytokines. To prove this hypothesis, we conducted an expression profile in HCT 116 cells treated with or without M1 and focused on the mRNA expression of 112 cytokines and chemokines in the array data based on related research on their induction of the bystander killing effect (14) and whole cellular cytokine and chemokine signaling pathways (14,19). We ranked the cytokines and chemokines by the expression ratio upon M1 treatment compared with the control group (Fig.…”

“…Although oncolytic viruses selectively kill tumor cells, the outcome of infection with them varies a lot due to the complex interactions between the virus and the host defense system (8). This fact has led to efforts aimed at increasing the effects of oncolytic viruses by genetically modifying or combining them with chemical sensitizers (1,2,(9)(10)(11)(12)(13)(14). This fact has also prompted us to test whether combining M1 with various chemical compounds enhances the oncolytic effect in refractory tumor cells in which M1 inhibits less than 25% of cell viability (15).…”

Trial Watch—Oncolytic viruses and cancer therapy

“…Among this abundant literature, we found of especial interest the works of (1) Arulanandam and colleagues (Ottawa Hospital Research Institute, Ottawa, Canada), who discovered that a transcriptional modulator operating downstream of vascular endothelial growth factor receptors (VEGFRs) 208,209 suppresses Type I interferon (IFN) responses, 210 hence sensitizing the tumor vasculature to infection by oncolytic viruses, 211 and found that microtubule-destabilizing agents commonly employed in the clinic (e.g., paclitaxel) 212,213 synergize with oncolytic virotherapy by disrupting the translation of Type I IFN-coding mRNAs and by exacerbating the demise of cancer cells provoked by the cytopathic effect; 214 (2) Nishio and collaborators (Baylor College of Medicine, Houston, TX, US), who reported that an oncolytic adenovirus genetically engineered to express interleukin-15 (IL-15) and chemokine (C-C motif) ligand 5 (CCL5, also known as RANTES) improved the therapeutic potential of adoptively transferred T cells expressing a chimeric antigen receptor (CAR) 215,216 [218][219][220][221][222] a means to boost the replication (and hence the efficacy) of an oncolytic HSV-1 strain; 223 (4) Parrish and co-authors (St James's University Hospital, Leeds, UK), who discovered that an oncolytic reovirus enhances the capacity of the FDA-approved CD20-targeting monoclonal antibody rituximab 224,225 to stimulate antibody-dependent cellular cytotoxicity; 226 , who discovered that autonomous parvoviruses are endowed with a rather advantageous feature for the development of novel oncolytic virotherapies, namely, they neither trigger nor inhibit Type I IFN responses in normal and malignant cells; 236 (11) Zloza and coauthors (Rush University Medical Center, Chicago, IL, US), who suggested that the downregulation of leukocyte immunoglobulin-like receptor, subfamily B (with TM and ITIM domains), member 1 (LILRB1, also known as ILT2) in peripheral blood mononuclear cells may constitute a reliable biomarker of therapeutic responses to oncolytic virotherapy in cancer patients; 237 (12) Liikanen and colleagues (University of Helsinki, Helsinki, Finland), who propose that the circulating levels of the damage-associated molecular pattern high mobility group box 1 (HMGB1) [238][239][240][241] at baseline may constitute a robust prognostic factor as well as a predictive indicator of disease control up...…”