VEGF-Mediated Induction of PRD1-BF1/Blimp1 Expression Sensitizes Tumor Vasculature to Oncolytic Virus Infection

Arulanandam, Rozanne; Batenchuk, Cory; Angarita, Fernando A.; Ottolino‐Perry, Kathryn; Cousineau, Sophie; Mottashed, Amelia; Burgess, Emma; Falls, Theresa; Silva, Naomi De; Tsang, Jovian; Howe, Grant A.; Bourgeois-Daigneault, Marie-Claude; Conrad, David P.; Daneshmand, Manijeh; Breitbach, Caroline J.; Kirn, David H.; Raptis, Leda; Sad, Subash; Atkins, Harold L.; Huh, Michael S.; Diallo, Jean-Simon; Lichty, Brian D.; Ilkow, Carolina S.; Bœuf, Fabrice Le; Addison, Christina L.; McCart, J. Andrea; Bell, John C.

doi:10.1016/j.ccell.2015.06.009

Cited by 83 publications

(76 citation statements)

References 48 publications

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“…To determine whether Blimp1 can be induced indirectly by secreted factors, we measured Blimp1 levels in PDAC cells cultured with conditioned media from hypoxia-treated cells or recombinant VEGF-A which has been shown to induce Blimp1 in endothelial cells (41). In both cases, we did not observe robust Blimp1 induction (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

BLIMP1 Induces Transient Metastatic Heterogeneity in Pancreatic Cancer

et al. 2017

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Pancreatic ductal adenocarcinoma (PDAC) is one of the most metastatic and deadly cancers. Despite the clinical significance of metastatic spread, our understanding of molecular mechanisms that drive PDAC metastatic ability remains limited. Using a novel genetically engineered mouse model of human PDAC, we uncover a transient subpopulation of cancer cells with exceptionally high metastatic ability. Global gene expression profiling and functional analyses uncovered the transcription factor Blimp1 as a key driver of PDAC metastasis. The highly metastatic PDAC subpopulation is enriched for hypoxia-induced genes and hypoxia-mediated induction of Blimp1 contributes to the regulation of a subset of hypoxia-associated gene expression programs. These findings support a model in which up-regulation of Blimp1 links microenvironmental cues to a metastatic stem cell character.

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Section: Resultsmentioning

confidence: 99%

BLIMP1 Induces Transient Metastatic Heterogeneity in Pancreatic Cancer

et al. 2017

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“…The expression of VEGFR, which promotes tumor angiogenesis and progression, sensitizes the tumor vasculature to infection by oncolytic VACV (80). However, the TME coordinately inhibits protective antitumor immune responses that are crucial to the overall therapeutic efficacy of OVs applied to the immunocompetent (tumor-bearing) host.…”

Section: Current Strategies In Oncolytic Immunotherapymentioning

confidence: 99%

Oncolytic Immunotherapy: Conceptual Evolution, Current Strategies, and Future Perspectives

et al. 2017

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The concept of oncolytic virus (OV)-mediated cancer therapy has been shifted from an operational virotherapy paradigm to an immunotherapy. OVs often induce immunogenic cell death (ICD) of cancer cells, and they may interact directly with immune cells as well to prime antitumor immunity. We and others have developed a number of strategies to further stimulate antitumor immunity and to productively modulate the tumor microenvironment (TME) for potent and sustained antitumor immune cell activity. First, OVs have been engineered or combined with other ICD inducers to promote more effective T cell cross-priming, and in many cases, the breaking of functional immune tolerance. Second, OVs may be armed to express Th1-stimulatory cytokines/chemokines or costimulators to recruit and sustain the potent antitumor immunity into the TME to focus their therapeutic activity within the sites of disease. Third, combinations of OV with immunomodulatory drugs or antibodies that recondition the TME have proven to be highly promising in early studies. Fourth, combinations of OVs with other immunotherapeutic regimens (such as prime-boost cancer vaccines, CAR T cells; armed with bispecific T-cell engagers) have also yielded promising preliminary findings. Finally, OVs have been combined with immune checkpoint blockade, with robust antitumor efficacy being observed in pilot evaluations. Despite some expected hurdles for the rapid translation of OV-based state-of-the-art protocols, we believe that a cohort of these novel approaches will join the repertoire of standard cancer treatment options in the near future.

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“…(81) This has led to the idea that initial inhibition of immune responses could facilitate viral proliferation. (82) Besides the immune system, other proteins such as vascular endothelial growth factor, whose presence was shown to limit efficacy of an OV derived from HSV,(83) seem to play a role in the viral replication.…”

Section: Current Challengesmentioning

confidence: 99%

The Role of Oncolytic Viruses in the Treatment of Melanoma

et al. 2018

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Talimogene laherparepvec (T-VEC) is the first OV approved for the treatment of melanoma and presents new challenges as it enters the clinical setting. Several other OVs are at various stages of clinical and pre-clinical development for the treatment of melanoma. Reports from phase Ib-III clinical trials combining T-VEC with checkpoint blockade are encouraging and demonstrate potential added benefit of combination immunotherapy. OVs have recently emerged as a standard treatment option for patients with advanced melanoma. Several OVs and therapeutic combinations are in development. Immunooncolytic virotherapy combined with immune checkpoint inhibitors is promising for the treatment of advanced melanoma.

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VEGF-Mediated Induction of PRD1-BF1/Blimp1 Expression Sensitizes Tumor Vasculature to Oncolytic Virus Infection

Cited by 83 publications

References 48 publications

BLIMP1 Induces Transient Metastatic Heterogeneity in Pancreatic Cancer

BLIMP1 Induces Transient Metastatic Heterogeneity in Pancreatic Cancer

Oncolytic Immunotherapy: Conceptual Evolution, Current Strategies, and Future Perspectives

The Role of Oncolytic Viruses in the Treatment of Melanoma

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