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      Current State of Dendritic Cell-Based Immunotherapy: Opportunities for in vitro Antigen Loading of Different DC Subsets?

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          Abstract

          Dendritic cell (DC) based cancer immunotherapy aims at the activation of the immune system, and in particular tumor-specific cytotoxic T lymphocytes (CTLs) to eradicate the tumor. DCs represent a heterogeneous cell population, including conventional DCs (cDCs), consisting of cDC1s, cDC2s, plasmacytoid DCs (pDCs), and monocyte-derived DCs (moDCs). These DC subsets differ both in ontogeny and functional properties, such as the capacity to induce CD4 + and CD8 + T-cell activation. MoDCs are most frequently used for vaccination purposes, based on technical aspects such as availability and in vitro expansion. However, whether moDCs are superior over other DC subsets in inducing anti-tumor immune responses, is unknown, and likely depends on tumor type and composition of the tumor microenvironment. In this review, we discuss cellular aspects essential for DC vaccination efficacy, and the most recent findings on different DC subsets that could be used for DC-based cancer immunotherapy. This can prove valuable for the future design of more effective DC vaccines by choosing different DC subsets, and sheds light on the working mechanism of DC immunotherapy.

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          Expansion and Activation of CD103(+) Dendritic Cell Progenitors at the Tumor Site Enhances Tumor Responses to Therapeutic PD-L1 and BRAF Inhibition.

          Hélène Salmon, Juliana Idoyaga, Adeeb Rahman … (2016)
          Large numbers of melanoma lesions develop resistance to targeted inhibition of mutant BRAF or fail to respond to checkpoint blockade. We explored whether modulation of intratumoral antigen-presenting cells (APCs) could increase responses to these therapies. Using mouse melanoma models, we found that CD103(+) dendritic cells (DCs) were the only APCs transporting intact antigens to the lymph nodes and priming tumor-specific CD8(+) T cells. CD103(+) DCs were required to promote anti-tumoral effects upon blockade of the checkpoint ligand PD-L1; however, PD-L1 inhibition only led to partial responses. Systemic administration of the growth factor FLT3L followed by intratumoral poly I:C injections expanded and activated CD103(+) DC progenitors in the tumor, enhancing responses to BRAF and PD-L1 blockade and protecting mice from tumor rechallenge. Thus, the paucity of activated CD103(+) DCs in tumors limits checkpoint-blockade efficacy and combined FLT3L and poly I:C therapy can enhance tumor responses to checkpoint and BRAF blockade.
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            Decisions about dendritic cells: past, present, and future.

            Ralph M. Steinman (2012)
            A properly functioning adaptive immune system signifies the best features of life. It is diverse beyond compare, tolerant without fail, and capable of behaving appropriately with a myriad of infections and other challenges. Dendritic cells are required to explain how this remarkable system is energized and directed. I frame this article in terms of the major decisions that my colleagues and I have made in dendritic cell science and some of the guiding themes at the time the decisions were made. As a result of progress worldwide, there is now evidence of a central role for dendritic cells in initiating antigen-specific immunity and tolerance. The in vivo distribution and development of a previously unrecognized white cell lineage is better understood, as is the importance of dendritic cell maturation to link innate and adaptive immunity in response to many stimuli. Our current focus is on antigen uptake receptors on dendritic cells. These receptors enable experiments involving selective targeting of antigens in situ and new approaches to vaccine design in preclinical and clinical systems.
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              Mapping the human DC lineage through the integration of high-dimensional techniques

              Peter Chi Ee See, Charles-Antoine Dutertre, Jinmiao Chen … (2017)
              Dendritic cells (DC) are professional antigen-presenting cells that orchestrate immune responses. The human DC population comprises two main functionally specialized lineages, whose origins and differentiation pathways remain incompletely defined. Here, we combine two high-dimensional technologies—single-cell mRNA sequencing and cytometry by time-of-flight (CyTOF), to identify human blood CD123+CD33+CD45RA+ DC precursors (pre-DC). Pre-DC share surface markers with plasmacytoid DC (pDC) but have distinct functional properties that were previously attributed to pDC. Tracing the differentiation of DC from the bone marrow to the peripheral blood revealed that the pre-DC compartment contains distinct lineage-committed subpopulations, including one early uncommitted CD123high pre-DC subset and two CD45RA+CD123low lineage-committed subsets exhibiting functional differences. The discovery of multiple committed pre-DC populations opens promising new avenues for the therapeutic exploitation of DC subset-specific targeting.
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                Author and article information

                Contributors
                Journal
                Journal ID (nlm-ta): Front Immunol
                Journal ID (iso-abbrev): Front Immunol
                Journal ID (publisher-id): Front. Immunol.
                Title: Frontiers in Immunology
                Publisher: Frontiers Media S.A.
                ISSN (Electronic): 1664-3224
                Publication date (Electronic): 03 December 2018
                Publication date Collection: 2018
                Volume: 9
                Electronic Location Identifier: 2804
                Affiliations
                [1] 1Department of Pulmonary Medicine, Erasmus Medical Center , Rotterdam, Netherlands
                [2] 2Erasmus Cancer Institute, Erasmus Medical Center , Rotterdam, Netherlands
                Author notes

                Edited by: Diana Dudziak, Universitätsklinikum Erlangen, Germany

                Reviewed by: Katsuaki Sato, University of Miyazaki, Japan; Richard A. Kroczek, Robert Koch Institute, Germany

                *Correspondence: Heleen Vroman h.vroman@ 123456erasmusmc.nl

                This article was submitted to Antigen Presenting Cell Biology, a section of the journal Frontiers in Immunology

                Article
                DOI: 10.3389/fimmu.2018.02804
                PMC ID: 6287551
                PubMed ID: 29403488
                SO-VID: 73b74f32-9044-49ef-bd0d-2c094969a76e
                Copyright © Copyright © 2018 Huber, Dammeijer, Aerts and Vroman.
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                Date received : 16 July 2018
                Date accepted : 14 November 2018
                Page count
                Figures: 1, Tables: 1, Equations: 0, References: 98, Pages: 9, Words: 7261
                Categories
                Subject: Immunology
                Subject: Mini Review

                ScienceOpen disciplines: Immunology
                Keywords: dendritic cell (dc),immunotherapy,dc subsets,t cell responses,tumor immunology
                Data availability:
                ScienceOpen disciplines: Immunology
                Keywords: dendritic cell (dc), immunotherapy, dc subsets, t cell responses, tumor immunology

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