Blockade of Type I Interferon (IFN) Production by Retroviral Replicating Vectors and Reduced Tumor Cell Responses to IFN Likely Contribute To Tumor Selectivity

Lin, Amy; Burrascano, Cindy; Pettersson, Pär L.; Ibañez, Carlos E.; Gruber, Harry E.; Jolly, Douglas J.

doi:10.1128/jvi.02300-13

Cited by 20 publications

(26 citation statements)

References 45 publications

(48 reference statements)

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“…Figure 2C showed that U87-MG cells treated with exogenous IFNα induced OAS1 gene expression by more than 25,000-fold compared to naive U87-MG cells. As previously reported, 24 U87-MG cells infected with RRV-yCD2 (aka Toca 511) did not induce an IFN response that leads to robust induction of OAS1 expression as indicated by minimal change of OAS1 gene expression within 2-fold. Likewise, neither RRV-shGFP nor RRV-miRGFP induced IFN responses in U87-MG cells (Figure 2C).…”

Section: Resultssupporting

confidence: 70%

“…We have previously shown that RRV alone does not lead to type I IFN production from infected cells, and RRV particles can actively suppress type I IFN production 24 . This is different from most viral vectors including lentiviral vectors 34, 35.…”

Section: Discussionmentioning

confidence: 89%

“…We have previously shown that in vitro RRV does not trigger type I interferon (IFN) response 24 . However, type I IFN response induced by synthetic siRNA has been reported and also in some cases in which siRNA are processed intracellularly from shRNA 10, 25.…”

Section: Resultsmentioning

confidence: 99%

“…One of the advantages of generating siRNA from the miR30-derived shRNA backbone is potential further minimization of type I IFN response 9, 10. To determine whether miRshRNA expressed by RRV triggers type I IFN response, we used U87-MG cells which have previously been shown to be functional in producing type I IFN and responsive to type I IFN 24 . In this experiment, we infected U87-MG cells at a MOI of 0.1, 1, and 10 and obtained the cellular RNA 16 hr post infection.…”

Section: Resultsmentioning

confidence: 99%

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Retroviral Replicating Vector Delivery of miR-PDL1 Inhibits Immune Checkpoint PDL1 and Enhances Immune Responses In Vitro

Lin¹,

Twitty²,

Burnett³

et al. 2017

Molecular Therapy - Nucleic Acids

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Tumor cells express a number of immunosuppressive molecules that can suppress anti-tumor immune responses. Efficient delivery of small interfering RNAs to treat a wide range of diseases including cancers remains a challenge. Retroviral replicating vectors (RRV) can be used to stably and selectively introduce genetic material into cancer cells. Here, we designed RRV to express shRNA (RRV-shPDL1) or microRNA30-derived shRNA (RRV-miRPDL1) using Pol II or Pol III promoters to downregulate PDL1 in human cancer cells. We also designed RRV expressing cytosine deaminase (yCD2) and miRPDL1 for potential combinatorial therapy. Among various configurations tested, we showed that RRV-miRPDL1 vectors with Pol II or Pol III promoter replicated efficiently and exhibited sustained downregulation of PDL1 protein expression by more than 75% in human cancer cell lines with high expression of PDL1. Immunologic effects of RRV-miRPDL1 were assessed by a trans-suppression lymphocyte assay. In vitro data showed downregulation of PDL1+ tumor cells restored activation of CD8+ T cells and bio-equivalency compared to anti-PDL1 antibody treatment. These results suggest RRV-miRPDL1 may be an alternative therapeutic approach to enhance anti-tumor immunity by overcoming PDL1-induced immune suppression from within cancer cells and this approach may also be applicable to other cancer targets.

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Section: Resultssupporting

confidence: 70%

Section: Discussionmentioning

confidence: 89%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Retroviral Replicating Vector Delivery of miR-PDL1 Inhibits Immune Checkpoint PDL1 and Enhances Immune Responses In Vitro

Lin¹,

Twitty²,

Burnett³

et al. 2017

Molecular Therapy - Nucleic Acids

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“…Treated animals expressed elevated levels of FOXO3a, a negative regulator of IFN signaling, and increased depletion of CD4 + T cells was observed, although no changes in viral loads were detectable. During the infection of mice with murine retroviruses type I IFN is undetectable in the serum [74, 75] and Lin et al [76] recently showed, that Moloney Leukemia Virus (MLV)-based vectors directly block the production of type I IFN in pDCs. The molecular mechanism of this suppression remains currently unknown.…”

Section: Counter-regulation Of the Nk Cell Response By Retrovirusesmentioning

confidence: 99%

Insufficient natural killer cell responses against retroviruses: how to improve NK cell killing of retrovirus-infected cells

2016

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Natural killer (NK) cells belong to the innate immune system and protect against cancers and a variety of viruses including retroviruses by killing transformed or infected cells. They express activating and inhibitory receptors on their cell surface and often become activated after recognizing virus-infected cells. They have diverse antiviral effector functions like the release of cytotoxic granules, cytokine production and antibody dependent cellular cytotoxicity. The importance of NK cell activity in retroviral infections became evident due to the discovery of several viral strategies to escape recognition and elimination by NK cells. Mutational sequence polymorphisms as well as modulation of surface receptors and their ligands are mechanisms of the human immunodeficiency virus-1 to evade NK cell-mediated immune pressure. In Friend retrovirus infected mice the virus can manipulate molecular or cellular immune factors that in turn suppress the NK cell response. In this model NK cells lack cytokines for optimal activation and can be functionally suppressed by regulatory T cells. However, these inhibitory pathways can be overcome therapeutically to achieve full activation of NK cell responses and ultimately control dissemination of retroviral infection. One effective approach is to modulate the crosstalk between NK cells and dendritic cells, which produce NK cell-stimulating cytokines like type I interferons (IFN), IL-12, IL-15, and IL-18 upon retrovirus sensing or infection. Therapeutic administration of IFNα directly increases NK cell killing of retrovirus-infected cells. In addition, IL-2/anti-IL-2 complexes that direct IL-2 to NK cells have been shown to significantly improve control of retroviral infection by NK cells in vivo. In this review, we describe novel approaches to improve NK cell effector functions in retroviral infections. Immunotherapies that target NK cells of patients suffering from viral infections might be a promising treatment option for the future.

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Immunologic aspects of viral therapy for glioblastoma and implications for interactions with immunotherapies

et al. 2021

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Blockade of Type I Interferon (IFN) Production by Retroviral Replicating Vectors and Reduced Tumor Cell Responses to IFN Likely Contribute To Tumor Selectivity

Abstract: We developed a Moloney mouse leukemia virus (MLV)-based retroviral replicating vector (RRV),

Cited by 20 publications

References 45 publications

Retroviral Replicating Vector Delivery of miR-PDL1 Inhibits Immune Checkpoint PDL1 and Enhances Immune Responses In Vitro

Retroviral Replicating Vector Delivery of miR-PDL1 Inhibits Immune Checkpoint PDL1 and Enhances Immune Responses In Vitro

Insufficient natural killer cell responses against retroviruses: how to improve NK cell killing of retrovirus-infected cells

Immunologic aspects of viral therapy for glioblastoma and implications for interactions with immunotherapies

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