Synergistic anti-tumor effects between oncolytic vaccinia virus and paclitaxel are mediated by the IFN response and HMGB1

Abstract

Recent developments in the field of oncolytic or tumor-selective viruses have meant that the clinical applications of these agents are now being considered in more detail. Like most cancer therapies it is likely that they will be used primarily in combination with other therapeutics. Although several reports have shown that oncolytic viruses can synergize with chemotherapies within an infected cancer cell, it would be particularly important to determine whether factors released from infected cells could enhance the action of chemotherapies at a distance. Here, we demonstrate in vitro synergy between oncolytic vaccinia and taxanes. However, we also show, for the first time, that this synergy is at least partly due to the release of factors from the infected cells that are capable of sensitizing surrounding cells to chemotherapy. Several cellular factors were identified as being mediators of this bystander effect, including type I interferon released soon after infection and high-mobility group protein B1 (HMGB1) released after cell death. This represents the first description of these mechanisms for beneficial interactions between viral and traditional tumor therapies. These data may provide a direct basis for the design of clinical trials with agents currently in the clinic, as well as providing insight into the development of next generation viral vectors.

Multimodal immunogenic cancer cell death as a consequence of anticancer cytotoxic treatments

“…113 Recent studies delineated that oncolytic viruses such as vaccinia, measles, HSV-2, and adenovirus cause the release of HMGB1. 64,65,114,115,116,117 Although HMGB1 interacts with viral components and may modulate viral replication, 117 the molecular mechanisms of how each oncolytic virus differentially produces these DAMPs remain largely elusive.…”

Complementary Induction of Immunogenic Cell Death by Oncolytic Parvovirus H-1PV and Gemcitabine in Pancreatic Cancer

“…HMGB1 can function as a chemoattractant for immune cells, activating them upon binding to TLR2, TLR4, TLR9, and RAGE receptors, thereby initiating an adaptive immune response resulting in engagement of antigen-specific cytotoxic effectors (cytotoxic T lymphocytes [CTLs]) (67,72,82,83). Antitumor protection induced by oncolytic viruses also appears to rely on the release of HMGB1 (41,43). This is particularly the case for viruses enforced with immunostimulatory elements, as demonstrated by the ability of glycyrrhizin to completely block tumor regression induced by ganciclovir and adenoviral vectors encoding herpes simplex virus 1-thymidine kinase and cytokine Flt3L (Ad-TKϩGCV and Ad-Flt3L) in a glioblastoma model (84).…”

“…The release of ICD determinants upon infections in general, and by tumor cells infected with oncolytic viruses in particular, has started to draw attention (37)(38)(39)(40)(41)(42)(43). We hypothesized that triggering the adaptive anticancer activity by H-1PV-alone or in combination with gemcitabine-could be initiated by ICD determinants released from dying tumor cells.…”

Vaccinia Virus, a Promising New Therapeutic Agent for Pancreatic Cancer

“…VV kills cancer cells via a combination of necrosis and immunogenic apoptosis resulting in the release of damage associated molecular patterns [75][76][77][78] and pathogen associated molecular patterns [79][80][81] as well as the release of viral antigens into the tumor. This process leads to a strong inflammatory response that can overcome the immune suppression within the tumor microenvironment.…”