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      Generation of dendritic cell-based vaccine using high hydrostatic pressure for non-small cell lung cancer immunotherapy

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          Abstract

          High hydrostatic pressure (HHP) induces immunogenic death of tumor cells which confer protective anti-tumor immunity in vivo. Moreover, DC pulsed with HHP-treated tumor cells induced therapeutic effect in mouse cancer model. In this study, we tested the immunogenicity, stability and T cell stimulatory activity of human monocyte-derived dendritic cell (DC)-based HHP lung cancer vaccine generated in GMP compliant serum free medium using HHP 250 MPa. DC pulsed with HHP-killed lung cancer cells and poly(I:C) enhanced DC maturation, chemotactic migration and production of pro-inflammatory cytokines after 24h. Moreover, DC-based HHP lung cancer vaccine showed functional plasticity after transfer into serum-containing media and stimulation with LPS or CD40L after additional 24h. LPS and CD40L stimulation further differentially enhanced the expression of costimulatory molecules and production of IL-12p70. DC-based HHP lung cancer vaccine decreased the number of CD4 +CD25 +Foxp3 + T regulatory cells and stimulated IFN-γ-producing tumor antigen-specific CD4 + and CD8 + T cells from non-small cell lung cancer (NSCLC) patients. Tumor antigen specific CD8 + and CD4 + T cell responses were detected in NSCLC patient’s against a selected tumor antigens expressed by lung cancer cell lines used for the vaccine generation. We also showed for the first time that protein antigen from HHP-killed lung cancer cells is processed and presented by DC to CD8 + T cells. Our results represent important preclinical data for ongoing NSCLC Phase I/II clinical trial using DC-based active cellular immunotherapy (DCVAC/LuCa) in combination with chemotherapy and immune enhancers.

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          Most cited references39

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          Ligation of CD40 on dendritic cells triggers production of high levels of interleukin-12 and enhances T cell stimulatory capacity: T-T help via APC activation

          We investigated the possibility that T helper cells might enhance the stimulatory function of dendritic cells (DCs). We found that ligation of CD40 by CD40L triggers the production of extremely high levels of bioactive IL-12. Other stimuli such as microbial agents, TNF-alpha or LPS are much less effective or not at all. In addition, CD40L is the most potent stimulus in upregulating the expression of ICAM-1, CD80, and CD86 molecules on DCs. These effects of CD40 ligation result in an increased capacity of DCs to trigger proliferative responses and IFN- gamma production by T cells. These findings reveal a new role for CD40- CD40L interaction in regulating DC function and are relevant to design therapeutic strategies using cultured DCs.
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            Molecular characteristics of immunogenic cancer cell death.

            Apoptotic cell death is initiated by a morphologically homogenous entity that was considered to be non-immunogenic and non-inflammatory in nature. However, recent advances suggest that apoptosis, under certain circumstances, can be immunogenic. In particular, some characteristics of the plasma membrane, acquired at preapoptotic stage, can cause immune effectors to recognize and attack preapoptotic tumor cells. The signals that mediate the immunogenicity of tumor cells involve elements of the DNA damage response (such as ataxia telangiectasia mutated and p53 activation), elements of the endoplasmic reticulum stress response (such as eukaryotic initiation factor 2alpha phosphorylation), as well as elements of the apoptotic response (such as caspase activation). Depending on the signal-transduction pathway, tumor cells responding to chemotherapy or radiotherapy can express 'danger' and 'eat me' signals on the cell surface (such as NKG2D ligands, heat-shock proteins and calreticulin) or can secrete/release immunostimulatory factors (such as cytokines and high-mobility group box 1) to stimulate innate immune effectors. Likewise, the precise sequence of such events influences the 'decision' of the immune system to mount a cognate response or not. We therefore anticipate that the comprehension of the mechanisms governing the immunogenicity of cell death will have a profound impact on the design of anticancer therapies.
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              The role of CD40 and CD154/CD40L in dendritic cells.

              In this review, we focus on the function of CD40-CD40L (CD154) interactions in the regulation of dendritic cell (DC)-T cell and DC-B cell crosstalk. In addition, we examine differences and similarities between the CD40 signaling pathway in DCs and other innate immune cell receptors, and how these pathways integrate DC functions. As research into DC vaccines and immunotherapies progresses, further understanding of CD40 and DC function will advance the applicability of DCs in immunotherapy for human diseases.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                10 February 2017
                2017
                : 12
                : 2
                : e0171539
                Affiliations
                [1 ]SOTIO, Prague, Czech Republic
                [2 ]Department of Immunology, 2nd Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic
                [3 ]Thoracic and Lung Transplantation Division, 3rd Department of Surgery, 1st Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic
                Mie University Graduate School of Medicine, JAPAN
                Author notes

                Competing Interests: IA, NH, LS, OP and RS are employees of Sotio a.s., Prague, Czech Republic. This does not alter our adherence to PLOS ONE policies on sharing data and materials. The funder provided support in the form of salaries for authors [IA, NH, OP, LS, RS], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

                • Conceptualization: IA RS RL.

                • Formal analysis: NH OP.

                • Funding acquisition: RS.

                • Investigation: NH IA OP HM DM LS.

                • Methodology: LS IA NH OP DM.

                • Project administration: IA NH OP LS.

                • Resources: DM HM.

                • Supervision: IA RS RL.

                • Validation: IA NH OP LS DM HM.

                • Visualization: NH OP LS IA.

                • Writing – original draft: IA.

                • Writing – review & editing: IA RS RL.

                Article
                PONE-D-16-16151
                10.1371/journal.pone.0171539
                5302789
                28187172
                66a40030-d4d2-4e21-942d-d28388c52a51
                © 2017 Hradilova et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 22 May 2016
                : 22 January 2017
                Page count
                Figures: 4, Tables: 0, Pages: 18
                Funding
                The authors declare that this study was supported by Sotio a.s. This study was further supported by the Charles University in Prague, Czech Republic, project GAUK No. 458216 granted to OP. This does not alter our adherence to PLOS ONE policies on sharing data and materials. The specific roles of these authors are articulated in the 'author contributions' section.
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