Interferon-Mediated Tumor Resistance to Oncolytic Virotherapy

Ebrahimi, Safieh; Ghorbani, Elnaz; Khazaei, Majid; Ryzhikov, Mikhail; Azadmanesh, Kayhan; Hassanian, Seyed Mahdi

doi:10.1002/jcb.25917

Cited by 30 publications

(23 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Immunotherapies with OVs and immune checkpoint inhibitors showed renewed promises for cancer treatment. However, many tumors are resistant to OVs27, 28, 29, 30 or fail to respond to checkpoint inhibitors 31, 32. When cells are infected by OVs, the virus replication causes tremendous stress on the host cells 33 .…”

Section: Discussionmentioning

confidence: 99%

Overexpression of Smac by an Armed Vesicular Stomatitis Virus Overcomes Tumor Resistance

Turaga

et al. 2019

Molecular Therapy - Oncolytics

View full text Add to dashboard Cite

Despite reports of successful clinical cases, many tumors appear to resist infection by oncolytic viruses (OVs). To circumvent this problem, an armed vesicular stomatitis virus was constructed by inserting a transgene to express Smac/DIABLO during virus infection (VSV-S). Endogenous Smac in HeLa cells was diminished during wtVSV infection, whereas the Smac level was enhanced during VSV-S infection. Apoptosis was readily induced by VSV-S, but not wtVSV, infection. More importantly, the tumor volume was reduced to a larger extent when xenografts of 4T1 cells in BALB/c mice and OV-resistant T-47D cells in nude mice were intratumorally injected with VSV-S. VSV-S represents a novel mechanism to overcome tumor resistance, resulting in more significant tumor regression due to enhanced apoptosis.

show abstract

Section: Discussionmentioning

confidence: 99%

Overexpression of Smac by an Armed Vesicular Stomatitis Virus Overcomes Tumor Resistance

Turaga

et al. 2019

Molecular Therapy - Oncolytics

View full text Add to dashboard Cite

show abstract

“…Successful virotherapy of cancer is critically dependent on the ability of oncolytic viruses like vaccinia to overcome multiple defense barriers including the complement/antibody-mediated neutralization [1], the interferon-induced anti-viral state [2–5], as well as the innate and adaptive anti-viral immune mechanisms mediated by NK and T cells, respectively. Mesenchymal stem cells (MSC) represent a promising delivery vehicle that protects vaccinia virus from the effects of complement/neutralizing antibodies [6], while also having the unique ability to home to sites of inflammation and tumor growth [7].…”

Section: Introductionmentioning

confidence: 99%

Delivery of oncolytic vaccinia virus by matched allogeneic stem cells overcomes critical innate and adaptive immune barriers

et al. 2019

View full text Add to dashboard Cite

Background Previous studies have identified IFNγ as an important early barrier to oncolytic viruses including vaccinia. The existing innate and adaptive immune barriers restricting oncolytic virotherapy, however, can be overcome using autologous or allogeneic mesenchymal stem cells as carrier cells with unique immunosuppressive properties. Methods To test the ability of mesenchymal stem cells to overcome innate and adaptive immune barriers and to successfully deliver oncolytic vaccinia virus to tumor cells, we performed flow cytometry and virus plaque assay analysis of ex vivo co-cultures of stem cells infected with vaccinia virus in the presence of peripheral blood mononuclear cells from healthy donors. Comparative analysis was performed to establish statistically significant correlations and to evaluate the effect of stem cells on the activity of key immune cell populations. Results Here, we demonstrate that adipose-derived stem cells (ADSCs) have the potential to eradicate resistant tumor cells through a combination of potent virus amplification and sensitization of the tumor cells to virus infection. Moreover, the ADSCs demonstrate ability to function as a virus-amplifying Trojan horse in the presence of both autologous and allogeneic human PBMCs, which can be linked to the intrinsic immunosuppressive properties of stem cells and their unique potential to overcome innate and adaptive immune barriers. The clinical application of ready-to-use ex vivo expanded allogeneic stem cell lines, however, appears significantly restricted by patient-specific allogeneic differences associated with the induction of potent anti-stem cell cytotoxic and IFNγ responses. These allogeneic responses originate from both innate (NK)- and adaptive (T)- immune cells and might compromise therapeutic efficacy through direct elimination of the stem cells or the induction of an anti-viral state, which can block the potential of the Trojan horse to amplify and deliver vaccinia virus to the tumor. Conclusions Overall, our findings and data indicate the feasibility to establish simple and informative assays that capture critically important patient-specific differences in the immune responses to the virus and stem cells, which allows for proper patient-stem cell matching and enables the effective use of off-the-shelf allogeneic cell-based delivery platforms, thus providing a more practical and commercially viable alternative to the autologous stem cell approach. Electronic supplementary material The online version of this article (10.1186/s12967-019-1829-z) contains supplementary material, which is available to authorized users.

show abstract

“…It should thus be possible to combine mutant forms of different viral proteins in order to modulate both the induction of interferon and/or interferon response, and sensitivity to the response. As previously mentioned, this could well be of importance to optimize oncolytic viral strains to different tumor cell types (Randall and Goodbourn, 2008;Naik and Russell, 2009;Kaufman et al, 2015;Vaha-Koskela and Hinkkanen, 2014;Ebrahimi et al, 2017). Virus replication in the absence of exogenously added interferon was also briefly examined.…”

Section: Discussionmentioning

confidence: 99%

“…However, examples abound where interferon can still contribute to limiting oncolytic activity, as recently reviewed (Vaha-Koskela and Hinkkanen, 2014;Ebrahimi et al, 2017). The original model of reovirus oncolytic activity postulated that a decreased in the interferon-induced protein kinase PKR was responsible for the increased ability of Ras-transformed cells to allow reovirus replication resulting in cell lysis (Strong et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Multiple proteins differing between laboratory stocks of mammalian orthoreoviruses affect both virus sensitivity to interferon and induction of interferon production during infection

Lanoie

Lemay

2018

Virus Research

View full text Add to dashboard Cite

In the course of previous works, it was observed that the virus laboratory stock (T3D) differs in sequence from the virus encoded by the ten plasmids currently in use in many laboratories (T3D), and derived from a different original virus stock. Seven proteins are affected by these sequence differences. In the present study, replication of T3D was shown to be more sensitive to the antiviral effect of interferon. Infection by the T3D virus was also shown to induce the production of higher amount of β and α-interferons compared to T3D. Two proteins, the μ2 and λ2 proteins, were found to be responsible for increased sensitivity to interferon while both μ2 and λ1 are responsible for increased interferon secretion. Altogether this supports the idea that multiple reovirus proteins are involved in the control of induction of interferon and virus sensitivity to the interferon-induced response. While interrelated, interferon induction and sensitivity can be separated by defined gene combinations. While both μ2 and λ2 were previously suspected of a role in the control of the interferon response, other proteins are also likely involved, as first shown here for λ1. This also further stresses that due caution should be exerted when comparing different virus isolates with different genetic background.

show abstract

Interferon-Mediated Tumor Resistance to Oncolytic Virotherapy

Cited by 30 publications

References 52 publications

Overexpression of Smac by an Armed Vesicular Stomatitis Virus Overcomes Tumor Resistance

Overexpression of Smac by an Armed Vesicular Stomatitis Virus Overcomes Tumor Resistance

Delivery of oncolytic vaccinia virus by matched allogeneic stem cells overcomes critical innate and adaptive immune barriers

Multiple proteins differing between laboratory stocks of mammalian orthoreoviruses affect both virus sensitivity to interferon and induction of interferon production during infection

Contact Info

Product

Resources

About