Combined cytotoxic activity of an infectious, but non‐replicative herpes simplex virus type 1 and plasmacytoid dendritic cells against tumour cells

Thomann, Sabrina; Boscheinen, Jan B.; Vogel, Karin; Knipe, David M.; DeLuca, Neal A.; Groß, Stefanie; Schuler‐Thurner, Beatrice; Schuster, Philipp; Schmidt, Bárbara

doi:10.1111/imm.12509

Cited by 15 publications

(22 citation statements)

References 49 publications

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“…Another emerging viral vector is the Sendai virus due to its high transduction efficiency ex vivo and in vivo , augmented capacity to trigger antitumor immune responses and elicit DC maturation [ 345 , 346 ]. Along the same lines, exploring the properties of IFN-α produced by pDCs, infection of pDCs with a replication-deficient herpes simplex virus 1 (HSV-1) d 106S vaccine strain showed a robust cytotoxic effect against various melanoma cell lines that was equivalent or superior to the effects induced by synthetic TLR7 and TLR9 agonists [ 347 ].…”

Section: Type I Ifns In Cancer Gene Therapy: Targeting Tumor and Dendmentioning

confidence: 99%

Immunomodulatory and antitumor effects of type I interferons and their application in cancer therapy

et al. 2017

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During the last decades, the pleiotropic antitumor functions exerted by type I interferons (IFNs) have become universally acknowledged, especially their role in mediating interactions between the tumor and the immune system. Indeed, type I IFNs are now appreciated as a critical component of dendritic cell (DC) driven T cell responses to cancer. Here we focus on IFN-α and IFN-β, and their antitumor effects, impact on immune responses and their use as therapeutic agents. IFN-α/β share many properties, including activation of the JAK-STAT signaling pathway and induction of a variety of cellular phenotypes. For example, type I IFNs drive not only the high maturation status of DCs, but also have a direct impact in cytotoxic T lymphocytes, NK cell activation, induction of tumor cell death and inhibition of angiogenesis. A variety of stimuli, including some standard cancer treatments, promote the expression of endogenous IFN-α/β, which then participates as a fundamental component of immunogenic cell death. Systemic treatment with recombinant protein has been used for the treatment of melanoma. The induction of endogenous IFN-α/β has been tested, including stimulation through pattern recognition receptors. Gene therapies involving IFN-α/β have also been described. Thus, harnessing type I IFNs as an effective tool for cancer therapy continues to be studied.

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Section: Type I Ifns In Cancer Gene Therapy: Targeting Tumor and Dendmentioning

confidence: 99%

Immunomodulatory and antitumor effects of type I interferons and their application in cancer therapy

et al. 2017

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“…At 10–14 days, macrophages were infected with wild type HSV-1 (32), HSV-1 166v (33), HSV-1 d 106S, and HSV-1 d 106S-MelanA. MRC-5 fibroblasts (ATCC® CCL-171 TM ) and melanoma cell lines (IGR-37, IGR-39, ARST-1, ICNI-5li, SK-MEL30, LIWE-7) were cultivated as described (9).…”

Section: Methodsmentioning

confidence: 99%

“…Upon activation by Toll-like receptor (TLR) agonists, PDC induce a Th1-type immune response and contribute to T cell-mediated tumor regression. In this respect, we have shown that PDC develop strong killer-cell like activity against melanoma cells upon exposure to HSV-1 d 106S (9). This was similarly observed by others using Toll-like receptor 7 and 9 agonists as well as viral vaccines for stimulation of PDC (18–26).…”

Section: Introductionmentioning

confidence: 96%

“…HSV-1 d 106S expresses GFP, which can be replaced by other genes of interest via homologous recombination. Using eleven different melanoma cell lines, we have shown that HSV-1 d 106S is oncolytic, in particular if combined with plasmacytoid dendritic cells (PDC) (9). These cells are major producers of type I interferons (IFN) in the blood upon stimulation with herpes simplex or influenza viruses (10, 11).…”

Section: Introductionmentioning

confidence: 99%

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Generation of an Oncolytic Herpes Simplex Virus 1 Expressing Human MelanA

et al. 2019

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Robust anti-tumor immunity requires innate as well as adaptive immune responses. We have shown that plasmacytoid dendritic cells develop killer cell-like activity in melanoma cell cocultures after exposure to the infectious but replication-deficient herpes simplex virus 1 (HSV-1) d106S. To combine this innate effect with an enhanced adaptive immune response, the gene encoding human MelanA/MART-1 was inserted into HSV-1 d106S via homologous recombination to increase direct expression of this tumor antigen. Infection of Vero cells using this recombinant virus confirmed MelanA expression by Western blotting, flow cytometry, and immunofluorescence. HSV-1 d106S-MelanA induced expression of the transgene in fibroblast and melanoma cell lines not naturally expressing MelanA. Infection of a melanoma cell line with CRISPR-Cas9-mediated knockout of MelanA confirmed de novo expression of the transgene in the viral context. Dependent on MelanA expression, infected fibroblast and melanoma cell lines induced degranulation of HLA-matched MelanA-specific CD8+ T cells, followed by killing of infected cells. To study infection of immune cells, we exposed peripheral blood mononuclear cells and in vitro-differentiated macrophages to the parental HSV-1 d106S, resulting in expression of the transgene GFP in CD11c+ cells and macrophages. These data provide evidence that the application of MelanA-encoding HSV-1 d106S could enhance adaptive immune responses and re-direct MelanA-specific CD8+ T cells to tumor lesions, which have escaped adaptive immune responses via downregulation of their tumor antigen. Hence, HSV-1 d106S-MelanA harbors the potential to induce innate immune responses in conjunction with adaptive anti-tumor responses by CD8+ T cells, which should be evaluated in further studies.

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“…All cell lines were grown in RPMI 1640 medium (PAN Biotech, Aidenbach, Germany) supplemented with 10% (v/v) fetal calf serum (Sigma, Steinheim, Germany). AXBI, ARST-1, and ICNI-5li cell lines were (after informed consent) established from metastatic lesions of melanoma patients as described previously (approved by the ethics committee of the Medical Faculty, Friedrich-Alexander-Universität Erlangen-Nürnberg, EK 4602) [ 52 ]. These cell lines were grown in Dulbecco’s modified Eagle’s medium (Thermo Fisher, Waltham, MA, USA) supplemented with 10% (v/v) fetal calf serum (Sigma).…”

Section: Methodsmentioning

confidence: 99%

Hypertonicity-enforced BCL-2 addiction unleashes the cytotoxic potential of death receptors

et al. 2018

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Attempts to exploit the cytotoxic activity of death receptors (DR) for treating cancer have thus far been disappointing. DR activation in most malignant cells fails to trigger cell death and may even promote tumor growth by activating cell death-independent DR-associated signaling pathways. Overcoming apoptosis resistance is consequently a prerequisite for successful clinical exploitation of DR stimulation. Here we show that hyperosmotic stress in the tumor microenvironment unleashes the deadly potential of DRs by enforcing BCL-2 addiction of cancer cells. Hypertonicity robustly enhanced cytotoxicity of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and other DR ligands in various cancer entities. Initial events in TRAIL DR signaling remained unaffected, but hypertonic conditions unlocked activation of the mitochondrial death pathway and thus amplified the apoptotic signal. Mechanistically, we demonstrate that hyperosmotic stress imposed a BCL-2-addiction on cancer cells to safeguard the integrity of the outer mitochondrial membrane (OMM), essentially exhausting the protective capacity of BCL-2-like pro-survival proteins. Deprivation of these mitochondrial safeguards licensed DR-generated truncated BH3-interacting domain death agonist (tBID) to activate BCL-2-associated X protein (BAX) and initiated mitochondrial outer membrane permeabilization (MOMP). Our work highlights that hyperosmotic stress in the tumor environment primes mitochondria for death and lowers the threshold for DR-induced apoptosis. Beyond TRAIL-based therapies, our findings could help to strengthen the efficacy of other apoptosis-inducing cancer treatment regimens.

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Combined cytotoxic activity of an infectious, but non‐replicative herpes simplex virus type 1 and plasmacytoid dendritic cells against tumour cells

Cited by 15 publications

References 49 publications

Immunomodulatory and antitumor effects of type I interferons and their application in cancer therapy

Immunomodulatory and antitumor effects of type I interferons and their application in cancer therapy

Generation of an Oncolytic Herpes Simplex Virus 1 Expressing Human MelanA

Hypertonicity-enforced BCL-2 addiction unleashes the cytotoxic potential of death receptors

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