Newcastle disease virus induces pro-inflammatory conditions and type I interferon for counter-acting Treg activity

Fournier, Philippe; Arnold, Annette; Wilden, Holger; Schirrmacher, Volker

doi:10.3892/ijo.2011.1265

Cited by 20 publications

(21 citation statements)

References 42 publications

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“…Notably, this effect was associated with relative reduction in the number of Tregs and marked enhancement of CD4 and CD8 effector to Treg ratios, which has been previously demonstrated to be a marker of a favorable immunological response to immunotherapy(29, 30). At present it is unclear what contributes to the relative reduction in the number of Tregs, although NDV-induced inflammatory cytokines have been previously suggested to have functions that could counter Treg activity (31). There is also a possibility that not all of the infiltrating FoxP3- CD4+ cells exhibit effector functions, as FoxP3- regulatory T cells have been previously reported (32).…”

Section: Discussionmentioning

confidence: 99%

Localized Oncolytic Virotherapy Overcomes Systemic Tumor Resistance to Immune Checkpoint Blockade Immunotherapy

et al. 2014

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Preexisting lymphocytic infiltration of tumors is associated with superior prognostic outcomes in a variety of cancers. Recent studies also suggest that lymphocytic responses may identify patients more likely to benefit from therapies targeting immune checkpoints, suggesting that therapeutic efficacy of immune checkpoint blockade can be enhanced through strategies that induce tumor inflammation. To achieve this effect, here we explored the immunotherapeutic potential of oncolytic Newcastle Disease Virus (NDV). We find that localized intratumoral therapy of B16 melanoma with NDV induces inflammatory responses leading to lymphocytic infiltrates and anti-tumor effect in distant (non-virally injected) tumors without distant virus spread. The inflammatory effect coincided with distant tumor infiltration with tumor-specific CD4+ and CD8+ T cells, which was dependent on the identity of the virus-injected tumor. Combination therapy with localized NDV and systemic CTLA-4 blockade led to rejection of pre-established distant tumors and protection from tumor re-challenge in poorly-immunogenic tumor models, irrespective of tumor cell line sensitivity to NDV-mediated lysis. Therapeutic effect was associated with marked distant tumor infiltration with activated CD8+ and CD4+ effector but not regulatory T cells, and was dependent on CD8+ cells, NK cells and type I interferon. Our findings demonstrate that localized therapy with oncolytic NDV induces inflammatory immune infiltrates in distant tumors, making them susceptible to systemic therapy with immunomodulatory antibodies, which provides a strong rationale for investigation of such combination therapies in clinic.

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Section: Discussionmentioning

confidence: 99%

Localized Oncolytic Virotherapy Overcomes Systemic Tumor Resistance to Immune Checkpoint Blockade Immunotherapy

et al. 2014

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“…Another study also demonstrated that genetically engineered NDV induced IFN-α and IFN-β in normal cells but only IFN-β in most tumor cells;28 in addition, IFN-α was shown to be expressed in mouse bronchoalveolar lavage (BAL) and mouse/human monocytes 29. Yet, there have been no reports demonstrating that IFN-λ is expressed higher than IFN-α/β in normal human cells after NDV infection.…”

Section: Resultsmentioning

confidence: 99%

Proinflammatory response induced by Newcastle disease virus in tumor and normal cells

Ginting¹,

Christian²,

Mathew³

2017

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Purpose: To investigate the specific role of immune responses induced by lentogenic Newcastle disease virus (NDV) for its antitumor effect. Materials and methods: NDV LaSota strain was used to infect the following human cells: non-small cell lung carcinoma (A549), glioblastoma (U87MG and T98G), mammary gland adenocarcinoma (MCF7 and MDA-MB-453), hepatocellular carcinoma (Huh7), transformed embryonic kidney cells (HEK293), primary monocytes, lung fibroblast (HF19), skin fibroblast (NB1RGB) and rat astroglia (RCR-1) at 0.001 multiplicity of infection. NDV-induced cytotoxicity and expression of proinflammatory cytokines were analyzed using 3-(4,5-dimethylthiazol-2-Yl)-2,5-diphenyltetrazolium bromide assay and multiplex enzyme-linked immunosorbent assay, respectively. Results: Tumor cells (A549, U87MG, T98G, Huh7, MDA-MB-453, and MCF7) showed viability of <44%, while normal cell lines HEK293, NB1RGB, and RCR-1 showed 84%, 73%, and 69% viability at 72 hours postinfection, respectively. Proinflammatory cytokine profiling showed that NDV mainly induced the secretion of interferon (IFN)-α, IFN-β, and IFN-λ in tumor cells and only IFN-λ in normal cells. In addition, NDV infection induced the production of interleukin (IL)-6 in most cells. Conclusion: Our findings suggest a new perspective regarding the role of IFN-λ and IL-6 in the mechanism of tumor selectivity and oncolysis of NDV. Keywords: Newcastle disease virus, oncolytic virus, interferons, cytokines IntroductionEvery year, mortality caused by cancer is increasing globally. This calls for novel therapeutic strategies.1 Use of oncolytic viruses represents a class of promising antitumor therapeutic options, primarily through the direct lysing of cancer cells and secondarily through the potential antitumor response induced by inflammation. [2][3][4][5][6] Newcastle disease virus (NDV) is a negative-strand RNA virus from the family Paramyxoviridae. This virus has been reported to be an effective oncolytic agent in vitro and in vivo against many types of solid tumors such as hepatocellular carcinoma, pancreatic adenocarcinoma, melanoma, pleural mesothelioma, colorectal carcinoma, renal carcinoma, glioblastoma and many others, 5,7-13 as well as in clinical studies in patients with glioblastoma multiforme, colorectal carcinoma, non-small cell lung carcinoma, renal carcinoma, breast adenocarcinoma, mesothelioma and pancreatic adenocarcinoma.14-18 NDV causes a disease that predominantly affects poultry, although infection in humans has been reported to cause conjunctivitis 19,20 and/or mild flu-like symptoms. [13][14][15][16][17]21 Based on their virulence on birds, NDV strains can be divided into 23-27 NDV is postulated to be a potent type I IFN inducer, but due to defective IFN signaling in tumor cells NDV replicates better in tumor cells. This has been the basis of tumor selective replication of NDV. 11,18,[28][29][30][31] The evidence for type I IFN production in vitro and in vivo after NDV infection has been obtained by measuring the level of IFN-α/β and the induction...

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“…Also, murine DCs upon infection by NDV differentiate into the immunogenic phenotype DC1 characterized by secretion of pro-inflammatory cytokines, in particular IL-12 and IFN-α and -β (44). Two receptor-initiated signaling cascades were involved: the first one is induced by triggering and upregulation of the intra-cellular cytoplasmic receptor RIG-1 upon recognition of viral non-capped RNA as ligand (45).…”

Section: Future Perspective: Combining Ndv With Bsabs and With Adoptimentioning

confidence: 99%

“…Two receptor-initiated signaling cascades were involved: the first one is induced by triggering and upregulation of the intra-cellular cytoplasmic receptor RIG-1 upon recognition of viral non-capped RNA as ligand (45). The second signal cascade involves cell-surface expressed type I IFN receptor (IFNAR), which initiates a feedback loop cell activation upon interaction with extra-cellular type I IFN as ligand (31, 44). RIG-1/RNA ligand interaction not only activates type I IFN, but also induces inflammasome activation for IL-1β production (46).…”

Section: Future Perspective: Combining Ndv With Bsabs and With Adoptimentioning

confidence: 99%

Multimodal Cancer Therapy Involving Oncolytic Newcastle Disease Virus, Autologous Immune Cells, and Bi-Specific Antibodies

Schirrmacher

Fournier

2014

Front. Oncol.

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This paper focuses on oncolytic Newcastle disease virus (NDV). This paper summarizes (i) the peculiarities of this virus as an anti-cancer and immune stimulatory agent and (ii) the approaches to further harness this virus as a vector to combat cancer. Special emphasis is given on combining virus therapy with cell therapy and on improving tumor targeting. The review will include some of the authors work on NDV, bi-specific antibodies, and cell therapy as building blocks for a new perspective of multimodal cancer therapy. The broad anti-tumor immune reactivation includes innate and adaptive, tumor antigen (TA) specific and TA independent activities

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Newcastle disease virus induces pro-inflammatory conditions and type I interferon for counter-acting Treg activity

Cited by 20 publications

References 42 publications

Localized Oncolytic Virotherapy Overcomes Systemic Tumor Resistance to Immune Checkpoint Blockade Immunotherapy

Localized Oncolytic Virotherapy Overcomes Systemic Tumor Resistance to Immune Checkpoint Blockade Immunotherapy

Proinflammatory response induced by Newcastle disease virus in tumor and normal cells

Multimodal Cancer Therapy Involving Oncolytic Newcastle Disease Virus, Autologous Immune Cells, and Bi-Specific Antibodies

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