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      Prospect of Plasmacytoid Dendritic Cells in Enhancing Anti-Tumor Immunity of Oncolytic Herpes Viruses

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          Abstract

          The major type I interferon-producing plasmacytoid dendritic cells (pDC) surround and infiltrate certain tumors like malignant melanoma, head and neck cancer, and ovarian and breast cancer. The presence of pDC in these tumors is associated with an unfavorable prognosis for the patients as long as these cells are unstimulated. Upon activation by synthetic Toll-like receptor agonists or viruses, however, pDC develop cytotoxic activities. Viruses have the additional advantage to augment cytotoxic activities of pDC via lytic replication in malignant lesions. These effects turn cold tumors into hotspots, recruiting further immune cells to the site of inflammation. Activated pDC contribute to cross-presentation of tumor-associated antigens by classical dendritic cells, which induce cytotoxic T-cells in particular in the presence of checkpoint inhibitors. The modification of oncolytic herpes viruses via genetic engineering favorably affects this process through the enhanced production of pro-inflammatory cytokines, curbing of tumor blood supply, and removal of extracellular barriers for efficient viral spread. Importantly, viral vectors may contribute to stimulation of memory-type adaptive immune responses through presentation of tumor-related neo- and/or self-antigens. Eventually, both replication-competent and replication-deficient herpes simplex virus 1 (HSV-1) may serve as vaccine vectors, which contribute to tumor regression by the stimulation of pDC and other dendritic cells in adjuvant and neo-adjuvant situations.

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          Most cited references87

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          NK Cells Stimulate Recruitment of cDC1 into the Tumor Microenvironment Promoting Cancer Immune Control

          Summary Conventional type 1 dendritic cells (cDC1) are critical for antitumor immunity, and their abundance within tumors is associated with immune-mediated rejection and the success of immunotherapy. Here, we show that cDC1 accumulation in mouse tumors often depends on natural killer (NK) cells that produce the cDC1 chemoattractants CCL5 and XCL1. Similarly, in human cancers, intratumoral CCL5, XCL1, and XCL2 transcripts closely correlate with gene signatures of both NK cells and cDC1 and are associated with increased overall patient survival. Notably, tumor production of prostaglandin E2 (PGE2) leads to evasion of the NK cell-cDC1 axis in part by impairing NK cell viability and chemokine production, as well as by causing downregulation of chemokine receptor expression in cDC1. Our findings reveal a cellular and molecular checkpoint for intratumoral cDC1 recruitment that is targeted by tumor-derived PGE2 for immune evasion and that could be exploited for cancer therapy.
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            Neoantigen vaccine generates intratumoral T cell responses in phase Ib glioblastoma trial

            Neoantigens, which are derived from tumour-specific protein-coding mutations, are exempt from central tolerance, can generate robust immune responses1,2 and can function as bona fide antigens that facilitate tumour rejection3. Here we demonstrate that a strategy that uses multi-epitope, personalized neoantigen vaccination, which has previously been tested in patients with high-risk melanoma4-6, is feasible for tumours such as glioblastoma, which typically have a relatively low mutation load1,7 and an immunologically 'cold' tumour microenvironment8. We used personalized neoantigen-targeting vaccines to immunize patients newly diagnosed with glioblastoma following surgical resection and conventional radiotherapy in a phase I/Ib study. Patients who did not receive dexamethasone-a highly potent corticosteroid that is frequently prescribed to treat cerebral oedema in patients with glioblastoma-generated circulating polyfunctional neoantigen-specific CD4+ and CD8+ T cell responses that were enriched in a memory phenotype and showed an increase in the number of tumour-infiltrating T cells. Using single-cell T cell receptor analysis, we provide evidence that neoantigen-specific T cells from the peripheral blood can migrate into an intracranial glioblastoma tumour. Neoantigen-targeting vaccines thus have the potential to favourably alter the immune milieu of glioblastoma.
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              The nature of the principal type 1 interferon-producing cells in human blood.

              Interferons (IFNs) are the most important cytokines in antiviral immune responses. "Natural IFN-producing cells" (IPCs) in human blood express CD4 and major histocompatibility complex class II proteins, but have not been isolated and further characterized because of their rarity, rapid apoptosis, and lack of lineage markers. Purified IPCs are here shown to be the CD4(+)CD11c- type 2 dendritic cell precursors (pDC2s), which produce 200 to 1000 times more IFN than other blood cells after microbial challenge. pDC2s are thus an effector cell type of the immune system, critical for antiviral and antitumor immune responses.
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                Author and article information

                Journal
                Cancers (Basel)
                Cancers (Basel)
                cancers
                Cancers
                MDPI
                2072-6694
                11 May 2019
                May 2019
                : 11
                : 5
                : 651
                Affiliations
                [1 ]Institute of Medical Microbiology and Hygiene, University of Regensburg, 93053 Regensburg, Germany; philipp1.schuster@ 123456ukr.de (P.S.); georg1.lindner@ 123456ukr.de (G.L.)
                [2 ]Institute of Clinical and Molecular Virology, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany; sabrina.thomann@ 123456arcor.de
                [3 ]Department of Dermatology, University Medical Center, 93053 Regensburg, Germany; sebastian.haferkamp@ 123456ukr.de
                [4 ]Institute of Clinical Microbiology and Hygiene, University Medical Center, 93053 Regensburg, Germany
                Author notes
                [* ]Correspondence: barbara.schmidt@ 123456ukr.de ; Tel.: +49-941-944-6404
                Article
                cancers-11-00651
                10.3390/cancers11050651
                6562787
                31083559
                f392e957-141e-45bf-be56-39654a3f0cdd
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 29 March 2019
                : 09 May 2019
                Categories
                Review

                plasmacytoid dendritic cells,herpes simplex virus 1,oncolytic virus

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