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Dendritic Cell Biology and Its Role in Tumor Immunotherapy Yingying Wang1,2,3,4† , Ying Xiang2,3†, Victoria W

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Dendritic Cell Biology and Its Role in Tumor Immunotherapy Yingying Wang1,2,3,4† , Ying Xiang2,3†, Victoria W Wang et al. Journal of Hematology & Oncology (2020) 13:107 https://doi.org/10.1186/s13045-020-00939-6 REVIEW Open Access Dendritic cell biology and its role in tumor immunotherapy Yingying Wang1,2,3,4† , Ying Xiang2,3†, Victoria W. Xin5†, Xian-Wang Wang2,6, Xiao-Chun Peng2,7, Xiao-Qin Liu2,3,8, Dong Wang2,3,NaLi9, Jun-Ting Cheng2,3, Yan-Ning Lyv10, Shu-Zhong Cui1, Zhaowu Ma2,3*, Qing Zhang11,12* and Hong-Wu Xin2,3,13* Abstract As crucial antigen presenting cells, dendritic cells (DCs) play a vital role in tumor immunotherapy. Taking into account the many recent advances in DC biology, we discuss how DCs (1) recognize pathogenic antigens with pattern recognition receptors through specific phagocytosis and through non-specific micropinocytosis, (2) process antigens into small peptides with proper sizes and sequences, and (3) present MHC-peptides to CD4+ and CD8+ T cells to initiate immune responses against invading microbes and aberrant host cells. During anti-tumor immune responses, DC-derived exosomes were discovered to participate in antigen presentation. T cell microvillar dynamics and TCR conformational changes were demonstrated upon DC antigen presentation. Caspase-11-driven hyperactive DCs were recently reported to convert effectors into memory T cells. DCs were also reported to crosstalk with NK cells. Additionally, DCs are the most important sentinel cells for immune surveillance in the tumor microenvironment. Alongside DC biology, we review the latest developments for DC- based tumor immunotherapy in preclinical studies and clinical trials. Personalized DC vaccine-induced T cell immunity, which targets tumor-specific antigens, has been demonstrated to be a promising form of tumor immunotherapy in patients with melanoma. Importantly, allogeneic-IgG-loaded and HLA-restricted neoantigen DC vaccines were discovered to have robust anti-tumor effects in mice. Our comprehensive review of DC biology and its role in tumor immunotherapy aids in the understanding of DCs as the mentors of T cells and as novel tumor immunotherapy cells with immense potential. Keywords: Dendritic cells (DCs), MHC, Immune cells, Tumor immunotherapy Introduction APCs and have many different subtypes. These subtypes Antigen presenting cells (APCs) play a significant role in have a variety of special functions in immunological pro- both innate and adapted immunity responses. The cat- cesses, such as initiating immune reactions, regulating egory of APCs consists of macrophages, dendritic cells immune responses, and maintaining those responses [2]. (DCs), and B lymphocytes [1]. DCs, first discovered by According to its ontogeny, a DC can be categorized as Ralph Steinman in 1973, are the most important of the either a conventional DC (cDC) or a plasmacytoid DC (pDC), as summarized in Table 1 [3]. Also, according to the developmental stage of the DC, it can be classified * Correspondence: [email protected]; [email protected]; into two major categories: immature and mature [4]. [email protected] †Yingying Wang, Ying Xiang and Victoria W. Xin contributed equally to this Most immature DCs reside on mucosal surfaces, with work. the skin and solid organs acting as sentinels to recognize 2 Laboratory of Oncology, Center for Molecular Medicine, School of Basic antigens. These DCs have a lower expression of major Medicine, Faculty of Medicine, Yangtze University, 1 Nanhuan Road, Jingzhou 434023, Hubei, China histocompatibility complex (MHC) I and MHC II, T cell 11State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen co-stimulation factors, and adhesion molecules [3]. University, Guangzhou 510275, China Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Wang et al. Journal of Hematology & Oncology (2020) 13:107 Page 2 of 18 Table 1 DC classification DC Identification basis Presence in vivo Main surface markers Secreted Function subtype molecules Mouse Human pDCs 120G8+, B220+, Circulate through the blood TLR7, TLR9, TLR12, RLR, TLR7, TLR9, RLR, STING, CD317, (1) Type I CD11c+, LY6C+, and lymphoid tissues STING, CLEC12A CLEC12A SIGLECH, interferons, (2) CD11b– B220, antigen BDC2*, presentation, (3) T BDC4* cell priming cDC1s cDC1s Thymus, spleen and lymph TLR2-, TLR4, TLR11– TLR1, TLR3, TLR6, TLR8, XCR1, Cross-priming (XCR1hiCD172low) nodes TLR13, STING, CLEC12A TLR10, STING, CLEC12A CLEC9A, (CD103), (CD8α), BDCA3* cDC2s cDC2s Thymus, spleen and lymph TLR1, TLR2, TLR4–TLR9, TLR1–TLR9, RLR, NLR, CD11b, CD4+ T cell (XCR1lowCD172hi) nodes TLR13, RLR, NLR, STING, STING, LEC4A, CLEC6A, SIRPa, priming CLEC4A, CLEC6A, CLEC7A, CLEC10A, (CD4), CLEC7A, (CLEC12A) CLEC12A (DCIR2) MoDCs CD11c+, Ly6C+, Differentiate from monocytes CD11c+, MHC-II+, CD11c+, MHC-II+, CD11b, Inflammation CD103 in peripheral tissues on CD11b+, Ly6C+, CD64+, CD11b+, Ly6C+, CD64+, CCR2, LY6C, inflammation. Resident in skin, CD206+, CD209+, CD206+, CD209+, CD115 lung, and intestine CD14+, CCR2+ CD14+, CCR2+, CD103+ Immature DCs do not secrete proinflammatory cyto- Specific phagocytosis kines. However, they are capable of migration. The critical approach of antigen uptake by DCs and When immature DCs uptake antigens, they shift to other immune cells is generally believed to be phagocyt- secondary lymphoid organs and present antigens to osis [7]. There are two important forms of phagocytosis: helper T cells or effector T cells to trigger specific cyto- microautophagy and chaperone-mediated autophagy toxic T lymphocyte (CTL) responses [5]. In the mean- (Fig. 1a). Microautophagy is initiated when the expres- time, they also gradually become more motile and sion of master regulator RAB5A is altered and the upregulate the expression of CC-chemokine receptors 7, MHC-II compartment (MIIC) is fused by the autophagy 8 (CCR7, 8) [6]. protein LC3. As a key endocytic protein, the master On the other hand, matured DCs have a reduced ability regulator RAB5A also has multiple physiological activ- to uptake and process antigens but have an enhanced mi- ities, such as promoting coherent and ballistic collective gration capacity. In addition, mature DCs were also re- motility, impacting junctional mechanics and monolayer ported to have an increased expression of various co- rigidity, and increasing endomembrane trafficking [9]. stimulatory molecules—for instance, CD40, CD70, and Chaperones, such as C-type lectins and Fc receptors, can CD80, as well as CD86—and an increased production of recognize antigens by targeting special ligands of apop- proinflammatory cytokines and chemokines [7, 8]. totic cells or pathogens. Afterwards, the endocytosis Here, we review the latest studies on DCs as the mentors process, mediated by clathrin, is induced, which places of T cells, with an emphasis on how DCs specifically antigens into antigen-processing compartments [10]. recognize, process, and present antigens to program T cells Here, we have highlighted the major mechanisms of for immune activation, suppression, or memorization. We chaperone-mediated autophagy. also highlight some recent developments that demonstrate theimmensepotentialofDCs in tumor immunotherapy. C-type lectin receptors (CLRs) Pattern-recognition receptors are critical components to immune responses. They recognize invading microbes Antigen recognition and internalization and induce protective immune responses to infection. DCs are highly dynamic, using their specific receptors to CLRs, a type of pattern-recognition receptor, are central recognize foreign invading antigens or aberrant self- to antifungal immunity. They are expressed on macro- antigens. DCs recognize antigens through pathogen- phages as well as DCs. Dectin-1, CLEC9, and DEC-205 associated molecular patterns (PAMPs) as well as (lymphocyte antigen 75) are all examples of CLRs [10]. danger-associated molecular patterns (DAMPs) through Specifically, the calcium-dependent carbohydrate recog- pattern recognition receptors (PRRs). DCs then uptake, nition domains (CRD) in CLRs recognize conserved fun- process, and present antigens to T cells to initiate im- gal cell-wall carbohydrates and their glycosylation mune responses (Fig. 1a). pattern, also known as the carbohydrate fingerprint [11]. Wang et al. Journal of Hematology & Oncology (2020) 13:107 Page 3 of 18 Table 2 Fc receptor classification and function FcR Type Affinity Function Fc Fc expression cells Short-term effects Long-term effects of domain signal Constitutive Inducible binding IgG FcR I I High Fc ITAM Monocytes Neutrophils, —— domains
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