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Table of Contents

    Topic review

    Dendritic Cell-Based Cancer Immunotherapy

    Subjects: Immunology
    View times: 19
    Submitted by: Takashi Nakayama

    Definition

    Cancer immunotherapy has now attracted much attention because of the recent success of immune checkpoint inhibitors. However, they are only beneficial in a limited fraction of patients most probably due to lack of sufficient CD8+ cytotoxic T-lymphocytes against tumor antigens in the host. In this regard, dendritic cells are useful tools to induce host immune responses against exogenous antigens. In particular, recently characterized cross-presenting dendritic cells are capable of inducing CD8+ cytotoxic T-lymphocytes against exogenous antigens such as tumor antigens and uniquely express the chemokine receptor XCR1. 

    1. Introduction

    Cancer is the major cause of death worldwide. Although surgery, radiation, and chemotherapy represent the three pillars of cancer therapy, the prognosis still remains poor in advanced stages of cancer often with metastases [1]. Thus, cancer immunotherapy, which aims to treat cancer by enhancing or inducing host immune responses to tumor cells, has long been hoped to become the fourth pillar of treatment. Historically, the potential therapeutic effect of host immune activity against cancer was first noted in the 19th century by Wilhelm Busch and Friedrich Fehleisen, who independently reported cancer regression after erysipelas infection [2]. Subsequently, William Coley developed Coley’s Toxin, a cocktail of killed bacteria, and used it to treat cancers such as osteosarcoma and lymphoma [2][3]. After that, Thomas and Burnet advanced the idea and proposed the cancer immunosurveillance hypothesis [2][4][5]. For decades, however, it remained difficult to induce or enhance host immune responses against tumor cells. Clinical trials such as cytokine-based immunotherapies or autologous/allogenic adoptive immune cell transfers were mostly disappointing [6]. Cancer vaccines that involve exogenous administration of tumor antigens with adjuvants to induce or enhance tumor-specific immune responses have also been tried, but mostly with unsatisfactory results [6]. Meanwhile, the concept of cancer immunosurveillance has also evolved into the theory of cancer immunoediting, which provides three phases for the complex interactions between tumors and the host immune system; namely, elimination, equilibrium, and escape [7][8]. Thus, it is now considered that, through these phases, tumor immunogenicity is edited and immunosuppressive mechanisms are acquired. However, the advent of immune checkpoint inhibitors has now revolutionized the field of cancer immunotherapy [2]. Furthermore, adoptive cell therapy employing autologous T cells with synthetic chimeric antigen receptors (CARs) has also been providing highly promising clinical results [9].
    Immune checkpoint molecules negatively regulate immune responses to maintain immune homeostasis by preventing overactivated immune responses or autoimmune responses [10][11]. In this context, cancer cells often utilize the immune checkpoint pathways to suppress host antitumor immune responses [10][11]. Thus, blocking the immune checkpoint molecules was considered as a strategy to enhance host immune responses to tumor cells. Indeed, the development of checkpoint inhibitors, such as anti-CTLA4 [12], anti-PD-1 [13], and anti-PD-L1 [14], has brought remarkable success in cancer immunotherapy. However, it has also been demonstrated that not all cancer patients favorably respond to the immune checkpoint inhibitors, possibly due to insufficient CD8+ cytotoxic T-lymphocytes (CTLs) against tumor cells in the host [10][11]. Thus, additional strategies may be needed to elicit tumor antigen-specific CD8+ CTLs in patients who do not sufficiently benefit from immune checkpoint inhibitors.
    It is now known that tumor cells express endogenous tumor antigens such as tumor-associated antigens (TAAs) (such as aberrantly expressed developmentally regulated antigens) and neoantigens generated by somatic mutations [15]. Therefore, if tumor antigen-specific CTLs are elicited in the host, they should be able to recognize and remove tumor cells. Thus, cancer vaccines are designed to induce tumor antigen-specific immune responses, particularly CD8+ CTLs [16]. Because dendritic cells (DCs) are professional antigen-presenting cells and have the unique ability to link innate and adaptive immunity, they have been regarded as the key target cells for cancer vaccine development. It is known that, upon antigen capture, DCs in peripheral tissues migrate to the draining lymph nodes where they present antigens to naive CD4+ and CD8+ T cells, resulting in the induction of effector T cells [17][18]. In the case of intracellular antigens, DCs process them and present antigen peptides through the major histocompatibility complex (MHC) class I pathway [17][18][19]. This leads to the induction of CD8+ CTLs. In the case of extracellular antigens, DCs usually process them and present antigen peptides through the MHC class II pathway that preferentially activates CD4+ T cells [18][19]. To induce CD8+ CTLs to extracellular antigens, therefore, the process called cross-presentation is needed to present antigen peptides via MHC class I [17]. Thus, cancer vaccines need to be preferentially processed by cross-presenting DCs. To this end, a number of adjuvants have been developed to activate cross-presenting DCs and have been shown to induce strong CD8+ CTL responses in animal models, yet very few have met the safety and efficacy requirement for human use [18]. Thus, it is of great importance to develop new vaccines and adjuvants that efficiently promote cross-presentation of extracellular antigens including tumor antigens for specific CD8+ CTL responses.
    Recent research progress has shown that there are several DC subsets with different roles in the induction of antigen-specific immune responses [18][20][21]. Among the DC subsets, conventional DC1s (cDC1s) are the ones that have the ability to cross-present extracellular antigens to naive CD8+ T cells [22][23][24]. Thus, the success of therapeutic cancer vaccines is now considered to depend on selective and efficient antigen delivery to cross-presenting cDC1s.

    2. DC Subsets and Their Functions

    DCs were originally recognized for their remarkable capacity to present antigens to T cells [25][26]. Thus, DCs are regarded as the primary professional antigen-presenting cells that serve as a major link between innate and adaptive immune responses. Upon antigen capture, DCs undergo a maturation process in which they upregulate the expression of MHC molecules, costimulatory molecules (CD80/86), cytokines, chemokines, and the chemokine receptor CCR7 [27][28]. Consequently, mature DCs migrate to regional lymphoid tissues via CCR7 and activate naïve T cells to differentiate to various effector T cells, including T helper (Th) 1 cells, Th2 cells, Th17 cells, T follicular helper (TFH) cells, regulatory T (Treg) cells, and CD8+ CTLs, resulting in various T-cell responses [19][27][28]. In this context, experimental evidence accumulated over the last two decades has revealed that DCs are heterogenous and there are different DC subsets that are specialized in priming different types of effector T cells [20]. Thus, individual DC subsets are able to skew immune responses according to their induction of different effector cell responses. Almost all DC subsets in humans and mice are known to express CD11c and can be distinguished by differential expression of cell surface markers and their immunological functions [18][20][21]. DCs are now broadly divided into four major subsets; namely, conventional DCs (cDCs), plasmacytoid DCs (pDCs), monocyte-derived DCs (moDCs), and Langerhans cells (LCs). cDCs are further subdivided into cDC1s and cDC2s. Analogous subsets have been identified in humans and mice [18][20][21]. The main phenotypic and functional characteristics of these five DC subsets are described below and summarized in Figure 1.
    Figure 1. Different subsets of dendritic cells.
    Five DC subsets are characterized by their surface phenotypes and functional properties: cDC1s (the signature markers: XCR1 and BDCA-3), cDC2s (the signature markers: CD11b, CD301b, and BDCA-1), pDCs (the signature markers: B220, Siglec-H, and BDCA-2), moDCs (the signature markers: CCR2 and CD64), and Langerhans cells (the signature markers: Langerin and EpCAM). cDC1s are specialized for CD8+ CTL and Th1 cell induction and thus mediate cellular immune responses. cDC2s present antigens to both CD4+ T cells and CD8+ T cells but preferentially induce CD4+ Th2 induction and are involved in humoral immune responses. pDCs abundantly produce type-I interferon and are critically involved in the induction of antiviral immune responses, especially in the gut. moDCs share functional characteristics with cDC1s and cDC2s, present antigens to CD4+ T cells and CD8+ T cells, and are widely involved in inflammatory responses. LCs present antigens to both CD4+ T cells and CD8+ T cells, but preferentially promote the differentiation of naïve CD4+ T cells into Th2cells, TFH cells, or Treg cells.

    3. Use of DEC205 and CLEC9A in cDC1-Targeting Vaccines

    Considerable efforts have been made to develop cancer vaccines that induce CD8+ CTL responses against cancer, but no sufficiently effective cancer vaccines are available so far. Because DCs were known to play a pivotal role in the induction of various immune responses, including CD8+ CTL responses, ex vivo-derived moDCs were also tried as DC-based cancer vaccines, but clinical outcomes were poor, possibly due to a limited capacity of in vitro-derived DCs to induce CD8+ CTL responses.
    Because recent studies have identified cDC1s as the key cross-presenting DC subset capable of inducing CD8+ CTLs [29][30][31], efforts have been focused on how to target cDC1s in antigen delivery. Because DEC-205 and CLEC9A are known to be highly expressed on cDC1s compared with other DC subsets (summarized in Table 1) [32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49], these molecules have been used as a possible target molecule to selectively deliver antigens to cDC1s [50]. DEC-205 is a C-type lectin receptor that acts as a recognition receptor for apoptotic and necrotic cells [51][52]. Although DEC-205 is expressed on all DC subsets, it is highly expressed on cDC1s and cDC2s [51][52][53][54][55]. DEC-205 is also reported to be weakly expressed on macrophages, NK cells, T cells, and B cells [51][52][53][54][55]. It was shown that coadministration of antigen-conjugated anti-DEC-205 antibodies with a combination of adjuvants such as complete Freund’s adjuvant, poly (I:C), or anti-CD40 antibody, efficiently induced antigen-specific IgG responses and CD8+ CTL responses [32][33][34][35]. Thus, antigen-conjugated anti-DEC-205 antibodies appeared to be capable of inducing humoral immune responses by cDC2s and cytotoxic immune responses by cDC1s. However, antigen-conjugated anti-DEC-205 antibodies alone without adjuvants failed to induce CD8+ CTL responses but rather induced immune tolerance [34][36]. CLEC9A is another C-type lectin receptor identified as the first receptor responsible for sensing necrotic cells [56][57][58]. CLEC9A is highly expressed on cDC1s and weakly expressed on pDCs and monocytes [59][60]. CLEC9A has also been shown to promote cross-presentation of dead cell-associated antigens [61][62]. Coadministration of antigen-conjugated anti-CLECA9 antibodies with anti-CD40 antibody efficiently induced CD8+ CTL responses against murine melanoma [37][38][39][40]. In the absence of adjuvants, however, antigen-conjugated anti-CLECA9 antibodies induced antigen-specific IgG responses, but not CD8+ CTL responses, and rather strongly induced Treg cell responses [41][42][43]. Thus, although DEC-205 and CLEC9A are promising surface molecules for targeted delivery of antigens to cDC1s, the vaccines based on these molecules require adjuvants for the efficient induction of CD8+ CTL responses. Furthermore, because DEC-205 and CLEC9A are also expressed on many other immune cells, their responses may be suppressive to CD8+ CTL responses.
    Table 1. Target molecules on cDC1s for CTL-inducing adjuvants.

    Target Molecule

    Type

    Expressing Cell

    Function

    Application (Ref)

    DEC-205

    C-type lectin receptor

    cDC1s, cDC2s, B cells, T cells, NK cells

    Antigen recognition (apoptotic and necrotic cells)

    [32][33][34][35][36]

    CLEC9A

    C-type lectin receptor

    cDC1s, some pDCs, monocytes

    Antigen recognition/endocytosis (cross-presentation)

    [37][38][39][40][41][42][43]

    XCR1

    Chemokine receptor

    cDC1s

    Cell migration

    [44][45][46][47][48][49]

    4. Differential Expression of Chemokine Receptors by DC Subsets

    Chemokines are a large family of small structurally related chemotactic cytokines that attract various leukocytes to their source of production via corresponding receptors [63][64]. Humans have around 50 chemokines, which are grouped into four subfamilies (CXC, CC, (X)C, and CX3C) by the motifs of the N-terminal conserved cysteine residues. Chemokine receptors belong to the seven-membrane G-protein-coupled receptor family, and there are 18 signal-transducing receptors in humans [63][64]. Chemokines play important roles in various biological processes, such as homeostatic migration and homing of lymphocytes, inflammatory infiltration of leukocytes, cell migration and homing during development, angiogenesis, wound healing, and even cancer metastasis [63][64][65].
    Chemokine receptors are known to be differentially expressed on various DC subsets. For example, immature DCs express a wide variety of chemokine receptors such as CCR1, CCR2, CCR5, and CCR6, consistent with their ability to respond to a wide range of chemokines [66]. Upon antigen capture, however, immature DCs downregulate the expression of these chemokine receptors and upregulate CCR7, which leads them to draining lymph nodes and other secondary lymphoid tissues where its ligands CCL19 and CCL21 are constitutively produced [67][68]. Furthermore, cDC1s selectively express XCR1 [69][70]; cDC2s mainly express CCR2 and CCR6 [71][72]; pDC mainly express CCR2, CCR5, CXCR3, and CXCR4 [73][74][75]; and moDCs mainly express CCR2 and CX3CR1 [76][77]. Thus, the chemokine receptors are useful for the characterization of various DC subsets, and they may also be possible candidates for targeted delivery of antigens to specific DC subsets. Chemokines may also be used as an adjuvant to attract specific DCs at the site of vaccination.

    The entry is from 10.3390/cancers13102495

    References

    1. Ganesh, K.; Massague, J. Targeting metastatic cancer. Nat. Med. 2021, 27, 34–44.
    2. Dobosz, P.; Dzieciatkowski, T. The Intriguing History of Cancer Immunotherapy. Front. Immunol. 2019, 10, 2965.
    3. Carlson, R.D.; Flickinger, J.C., Jr.; Snook, A.E. Talkin’ Toxins: From Coley’s to Modern Cancer Immunotherapy. Toxins (Basel) 2020, 12, 241.
    4. Burnet, F.M. The concept of immunological surveillance. Prog. Exp. Tumor Res. 1970, 13, 1–27.
    5. Thomas, L. On immunosurveillance in human cancer. Yale J. Biol. Med. 1982, 55, 329–333.
    6. Esfahani, K.; Roudaia, L.; Buhlaiga, N.; Del Rincon, S.V.; Papneja, N.; Miller, W.H., Jr. A review of cancer immunotherapy: From the past, to the present, to the future. Curr. Oncol. 2020, 27, S87–S97.
    7. Dunn, G.P.; Bruce, A.T.; Ikeda, H.; Old, L.J.; Schreiber, R.D. Cancer immunoediting: From immunosurveillance to tumor escape. Nat. Immunol. 2002, 3, 991–998.
    8. O’Donnell, J.S.; Teng, M.W.L.; Smyth, M.J. Cancer immunoediting and resistance to T cell-based immunotherapy. Nat. Rev. Clin. Oncol. 2019, 16, 151–167.
    9. Waldman, A.D.; Fritz, J.M.; Lenardo, M.J. A guide to cancer immunotherapy: From T cell basic science to clinical practice. Nat. Rev. Immunol. 2020, 20, 651–668.
    10. He, X.; Xu, C. Immune checkpoint signaling and cancer immunotherapy. Cell Res. 2020, 30, 660–669.
    11. Bonaventura, P.; Shekarian, T.; Alcazer, V.; Valladeau-Guilemond, J.; Valsesia-Wittmann, S.; Amigorena, S.; Caux, C.; Depil, S. Cold Tumors: A Therapeutic Challenge for Immunotherapy. Front. Immunol. 2019, 10, 168.
    12. Hodi, F.S.; O’Day, S.J.; McDermott, D.F.; Weber, R.W.; Sosman, J.A.; Haanen, J.B.; Gonzalez, R.; Robert, C.; Schadendorf, D.; Hassel, J.C.; et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 2010, 363, 711–723.
    13. Topalian, S.L.; Hodi, F.S.; Brahmer, J.R.; Gettinger, S.N.; Smith, D.C.; McDermott, D.F.; Powderly, J.D.; Carvajal, R.D.; Sosman, J.A.; Atkins, M.B.; et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 2012, 366, 2443–2454.
    14. Brahmer, J.R.; Tykodi, S.S.; Chow, L.Q.; Hwu, W.J.; Topalian, S.L.; Hwu, P.; Drake, C.G.; Camacho, L.H.; Kauh, J.; Odunsi, K.; et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 2012, 366, 2455–2465.
    15. van der Bruggen, P.; Traversari, C.; Chomez, P.; Lurquin, C.; De Plaen, E.; Van den Eynde, B.; Knuth, A.; Boon, T. A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science 1991, 254, 1643–1647.
    16. Saxena, M.; van der Burg, S.H.; Melief, C.J.M.; Bhardwaj, N. Therapeutic cancer vaccines. Nat. Rev. Cancer 2021, 1–19.
    17. Colbert, J.D.; Cruz, F.M.; Rock, K.L. Cross-presentation of exogenous antigens on MHC I molecules. Curr. Opin. Immunol. 2020, 64, 1–8.
    18. Wculek, S.K.; Cueto, F.J.; Mujal, A.M.; Melero, I.; Krummel, M.F.; Sancho, D. Dendritic cells in cancer immunology and immunotherapy. Nat. Rev. Immunol. 2020, 20, 7–24.
    19. Hilligan, K.L.; Ronchese, F. Antigen presentation by dendritic cells and their instruction of CD4+ T helper cell responses. Cell. Mol. Immunol. 2020, 17, 587–599.
    20. Eisenbarth, S.C. Dendritic cell subsets in T cell programming: Location dictates function. Nat. Rev. Immunol. 2019, 19, 89–103.
    21. Anderson, D.A., 3rd; Dutertre, C.A.; Ginhoux, F.; Murphy, K.M. Genetic models of human and mouse dendritic cell development and function. Nat. Rev. Immunol. 2021, 21, 101–115.
    22. Bottcher, J.P.; Reis e Sousa, C. The Role of Type 1 Conventional Dendritic Cells in Cancer Immunity. Trends Cancer 2018, 4, 784–792.
    23. den Haan, J.M.; Lehar, S.M.; Bevan, M.J. CD8(+) but not CD8(-) dendritic cells cross-prime cytotoxic T cells in vivo. J. Exp. Med. 2000, 192, 1685–1696.
    24. Pooley, J.L.; Heath, W.R.; Shortman, K. Cutting edge: Intravenous soluble antigen is presented to CD4 T cells by CD8- dendritic cells, but cross-presented to CD8 T cells by CD8+ dendritic cells. J. Immunol. 2001, 166, 5327–5330.
    25. Steinman, R.M.; Cohn, Z.A. Identification of a novel cell type in peripheral lymphoid organs of mice. I. Morphology, quantitation, tissue distribution. J. Exp. Med. 1973, 137, 1142–1162.
    26. Steinman, R.M.; Cohn, Z.A. Identification of a novel cell type in peripheral lymphoid organs of mice. II. Functional properties in vitro. J. Exp. Med. 1974, 139, 380–397.
    27. Guermonprez, P.; Valladeau, J.; Zitvogel, L.; Thery, C.; Amigorena, S. Antigen presentation and T cell stimulation by dendritic cells. Annu. Rev. Immunol. 2002, 20, 621–667.
    28. Patente, T.A.; Pinho, M.P.; Oliveira, A.A.; Evangelista, G.C.M.; Bergami-Santos, P.C.; Barbuto, J.A.M. Human Dendritic Cells: Their Heterogeneity and Clinical Application Potential in Cancer Immunotherapy. Front. Immunol. 2019, 9, 3176.
    29. Calabro, S.; Liu, D.; Gallman, A.; Nascimento, M.S.; Yu, Z.; Zhang, T.T.; Chen, P.; Zhang, B.; Xu, L.; Gowthaman, U.; et al. Differential Intrasplenic Migration of Dendritic Cell Subsets Tailors Adaptive Immunity. Cell Rep. 2016, 16, 2472–2485.
    30. Segura, E.; Durand, M.; Amigorena, S. Similar antigen cross-presentation capacity and phagocytic functions in all freshly isolated human lymphoid organ-resident dendritic cells. J. Exp. Med. 2013, 210, 1035–1047.
    31. Audsley, K.M.; McDonnell, A.M.; Waithman, J. Cross-Presenting XCR1(+) Dendritic Cells as Targets for Cancer Immunotherapy. Cells 2020, 9, 565.
    32. Dudziak, D.; Kamphorst, A.O.; Heidkamp, G.F.; Buchholz, V.R.; Trumpfheller, C.; Yamazaki, S.; Cheong, C.; Liu, K.; Lee, H.W.; Park, C.G.; et al. Differential antigen processing by dendritic cell subsets in vivo. Science 2007, 315, 107–111.
    33. Wang, B.; Zaidi, N.; He, L.Z.; Zhang, L.; Kuroiwa, J.M.; Keler, T.; Steinman, R.M. Targeting of the non-mutated tumor antigen HER2/neu to mature dendritic cells induces an integrated immune response that protects against breast cancer in mice. Breast Cancer Res. 2012, 14, R39.
    34. Idoyaga, J.; Lubkin, A.; Fiorese, C.; Lahoud, M.H.; Caminschi, I.; Huang, Y.; Rodriguez, A.; Clausen, B.E.; Park, C.G.; Trumpfheller, C.; et al. Comparable T helper 1 (Th1) and CD8 T-cell immunity by targeting HIV gag p24 to CD8 dendritic cells within antibodies to Langerin, DEC205, and Clec9A. Proc. Natl. Acad. Sci. USA 2011, 108, 2384–2389.
    35. Charalambous, A.; Oks, M.; Nchinda, G.; Yamazaki, S.; Steinman, R.M. Dendritic cell targeting of survivin protein in a xenogeneic form elicits strong CD4+ T cell immunity to mouse survivin. J. Immunol. 2006, 177, 8410–8421.
    36. Hawiger, D.; Inaba, K.; Dorsett, Y.; Guo, M.; Mahnke, K.; Rivera, M.; Ravetch, J.V.; Steinman, R.M.; Nussenzweig, M.C. Dendritic cells induce peripheral T cell unresponsiveness under steady state conditions in vivo. J. Exp. Med. 2001, 194, 769–779.
    37. Sancho, D.; Mourao-Sa, D.; Joffre, O.P.; Schulz, O.; Rogers, N.C.; Pennington, D.J.; Carlyle, J.R.; Reis e Sousa, C. Tumor therapy in mice via antigen targeting to a novel, DC-restricted C-type lectin. J. Clin. Invest. 2008, 118, 2098–2110.
    38. Tullett, K.M.; Leal Rojas, I.M.; Minoda, Y.; Tan, P.S.; Zhang, J.G.; Smith, C.; Khanna, R.; Shortman, K.; Caminschi, I.; Lahoud, M.H.; et al. Targeting CLEC9A delivers antigen to human CD141(+) DC for CD4(+) and CD8(+)T cell recognition. JCI Insight 2016, 1, e87102.
    39. Masterman, K.A.; Haigh, O.L.; Tullett, K.M.; Leal-Rojas, I.M.; Walpole, C.; Pearson, F.E.; Cebon, J.; Schmidt, C.; O’Brien, L.; Rosendahl, N.; et al. Human CLEC9A antibodies deliver NY-ESO-1 antigen to CD141(+) dendritic cells to activate naive and memory NY-ESO-1-specific CD8(+) T cells. J. Immunother. Cancer 2020, 8, e000691.
    40. Pearson, F.E.; Tullett, K.M.; Leal-Rojas, I.M.; Haigh, O.L.; Masterman, K.A.; Walpole, C.; Bridgeman, J.S.; McLaren, J.E.; Ladell, K.; Miners, K.; et al. Human CLEC9A antibodies deliver Wilms’ tumor 1 (WT1) antigen to CD141(+) dendritic cells to activate naive and memory WT1-specific CD8(+) T cells. Clin. Transl. Immunol. 2020, 9, e1141.
    41. Joffre, O.P.; Sancho, D.; Zelenay, S.; Keller, A.M.; Reis e Sousa, C. Efficient and versatile manipulation of the peripheral CD4+ T-cell compartment by antigen targeting to DNGR-1/CLEC9A. Eur. J. Immunol. 2010, 40, 1255–1265.
    42. Li, J.; Ahmet, F.; Sullivan, L.C.; Brooks, A.G.; Kent, S.J.; De Rose, R.; Salazar, A.M.; Reis e Sousa, C.; Shortman, K.; Lahoud, M.H.; et al. Antibodies targeting Clec9A promote strong humoral immunity without adjuvant in mice and non-human primates. Eur. J. Immunol. 2015, 45, 854–864.
    43. Caminschi, I.; Proietto, A.I.; Ahmet, F.; Kitsoulis, S.; Shin Teh, J.; Lo, J.C.; Rizzitelli, A.; Wu, L.; Vremec, D.; van Dommelen, S.L.; et al. The dendritic cell subtype-restricted C-type lectin Clec9A is a target for vaccine enhancement. Blood 2008, 112, 3264–3273.
    44. Mittal, D.; Vijayan, D.; Putz, E.M.; Aguilera, A.R.; Markey, K.A.; Straube, J.; Kazakoff, S.; Nutt, S.L.; Takeda, K.; Hill, G.R.; et al. Interleukin-12 from CD103(+) Batf3-Dependent Dendritic Cells Required for NK-Cell Suppression of Metastasis. Cancer Immunol. Res. 2018, 5, 1098–1108.
    45. Alexandre, Y.O.; Ghilas, S.; Sanchez, C.; Le Bon, A.; Crozat, K.; Dalod, M. XCR1+ dendritic cells promote memory CD8+ T cell recall upon secondary infections with Listeria monocytogenes or certain viruses. J. Exp. Med. 2016, 213, 75–92.
    46. Wong, J.L.; Berk, E.; Edwards, R.P.; Kalinski, P. IL-18-primed helper NK cells collaborate with dendritic cells to promote recruitment of effector CD8+ T cells to the tumor microenvironment. Cancer Res. 2013, 73, 4653–4662.
    47. Vu Manh, T.P.; Elhmouzi-Younes, J.; Urien, C.; Ruscanu, S.; Jouneau, L.; Bourge, M.; Moroldo, M.; Foucras, G.; Salmon, H.; Marty, H.; et al. Defining Mononuclear Phagocyte Subset Homology Across Several Distant Warm-Blooded Vertebrates Through Comparative Transcriptomics. Front. Immunol. 2015, 6, 299.
    48. Hartung, E.; Becker, M.; Bachem, A.; Reeg, N.; Jakel, A.; Hutloff, A.; Weber, H.; Weise, C.; Giesecke, C.; Henn, V.; et al. Induction of potent CD8 T cell cytotoxicity by specific targeting of antigen to cross-presenting dendritic cells in vivo via murine or human XCR1. J. Immunol. 2015, 194, 1069–1079.
    49. Mizumoto, Y.; Hemmi, H.; Katsuda, M.; Miyazawa, M.; Kitahata, Y.; Miyamoto, A.; Nakamori, M.; Ojima, T.; Matsuda, K.; Nakamura, M.; et al. Anticancer effects of chemokine-directed antigen delivery to a cross-presenting dendritic cell subset with immune checkpoint blockade. Br. J. Cancer 2020, 122, 1185–1193.
    50. Hossain, M.K.; Wall, K.A. Use of Dendritic Cell Receptors as Targets for Enhancing Anti-Cancer Immune Responses. Cancers (Basel) 2019, 11, 418.
    51. Jiang, W.; Swiggard, W.J.; Heufler, C.; Peng, M.; Mirza, A.; Steinman, R.M.; Nussenzweig, M.C. The receptor DEC-205 expressed by dendritic cells and thymic epithelial cells is involved in antigen processing. Nature 1995, 375, 151–155.
    52. Shrimpton, R.E.; Butler, M.; Morel, A.S.; Eren, E.; Hue, S.S.; Ritter, M.A. CD205 (DEC-205): A recognition receptor for apoptotic and necrotic self. Mol. Immunol. 2009, 46, 1229–1239.
    53. Guo, M.; Gong, S.; Maric, S.; Misulovin, Z.; Pack, M.; Mahnke, K.; Nussenzweig, M.C.; Steinman, R.M. A monoclonal antibody to the DEC-205 endocytosis receptor on human dendritic cells. Hum. Immunol. 2000, 61, 729–738.
    54. Kato, M.; Neil, T.K.; Fearnley, D.B.; McLellan, A.D.; Vuckovic, S.; Hart, D.N. Expression of multilectin receptors and comparative FITC-dextran uptake by human dendritic cells. Int. Immunol. 2000, 12, 1511–1519.
    55. Inaba, K.; Swiggard, W.J.; Inaba, M.; Meltzer, J.; Mirza, A.; Sasagawa, T.; Nussenzweig, M.C.; Steinman, R.M. Tissue distribution of the DEC-205 protein that is detected by the monoclonal antibody NLDC-145. I. Expression on dendritic cells and other subsets of mouse leukocytes. Cell. Immunol. 1995, 163, 148–156.
    56. Sancho, D.; Joffre, O.P.; Keller, A.M.; Rogers, N.C.; Martinez, D.; Hernanz-Falcon, P.; Rosewell, I.; Reis e Sousa, C. Identification of a dendritic cell receptor that couples sensing of necrosis to immunity. Nature 2009, 458, 899–903.
    57. Ahrens, S.; Zelenay, S.; Sancho, D.; Hanc, P.; Kjaer, S.; Feest, C.; Fletcher, G.; Durkin, C.; Postigo, A.; Skehel, M.; et al. F-actin is an evolutionarily conserved damage-associated molecular pattern recognized by DNGR-1, a receptor for dead cells. Immunity 2012, 36, 635–645.
    58. Zhang, J.G.; Czabotar, P.E.; Policheni, A.N.; Caminschi, I.; Wan, S.S.; Kitsoulis, S.; Tullett, K.M.; Robin, A.Y.; Brammananth, R.; van Delft, M.F.; et al. The dendritic cell receptor Clec9A binds damaged cells via exposed actin filaments. Immunity 2012, 36, 646–657.
    59. Huysamen, C.; Willment, J.A.; Dennehy, K.M.; Brown, G.D. CLEC9A is a novel activation C-type lectin-like receptor expressed on BDCA3+ dendritic cells and a subset of monocytes. J. Biol. Chem. 2008, 283, 16693–16701.
    60. Tullett, K.M.; Lahoud, M.H.; Radford, K.J. Harnessing Human Cross-Presenting CLEC9A(+)XCR1(+) Dendritic Cells for Immunotherapy. Front. Immunol. 2014, 5, 239.
    61. Iborra, S.; Izquierdo, H.M.; Martinez-Lopez, M.; Blanco-Menendez, N.; Reis e Sousa, C.; Sancho, D. The DC receptor DNGR-1 mediates cross-priming of CTLs during vaccinia virus infection in mice. J. Clin. Investig. 2012, 122, 1628–1643.
    62. Murray, D.P.; Watson, R.D.; Zezulka, A.V.; Murray, R.G.; Littler, W.A. Plasma catecholamine levels in acute myocardial infarction: Influence of beta-adrenergic blockade and relation to central hemodynamics. Am. Heart J. 1988, 115, 38–44.
    63. Zlotnik, A.; Yoshie, O. The chemokine superfamily revisited. Immunity 2012, 36, 705–716.
    64. Bachelerie, F.; Ben-Baruch, A.; Burkhardt, A.M.; Combadiere, C.; Farber, J.M.; Graham, G.J.; Horuk, R.; Sparre-Ulrich, A.H.; Locati, M.; Luster, A.D.; et al. International Union of Basic and Clinical Pharmacology. LXXXIX. Update on the extended family of chemokine receptors and introducing a new nomenclature for atypical chemokine receptors. Pharmacol. Rev. 2013, 66, 1–79.
    65. Yoshie, O.; Imai, T.; Nomiyama, H. Chemokines in immunity. Adv. Immunol. 2001, 78, 57–110.
    66. Sallusto, F.; Palermo, B.; Lenig, D.; Miettinen, M.; Matikainen, S.; Julkunen, I.; Forster, R.; Burgstahler, R.; Lipp, M.; Lanzavecchia, A. Distinct patterns and kinetics of chemokine production regulate dendritic cell function. Eur. J. Immunol. 1999, 29, 1617–1625.
    67. Dieu, M.C.; Vanbervliet, B.; Vicari, A.; Bridon, J.M.; Oldham, E.; Ait-Yahia, S.; Briere, F.; Zlotnik, A.; Lebecque, S.; Caux, C. Selective recruitment of immature and mature dendritic cells by distinct chemokines expressed in different anatomic sites. J. Exp. Med. 1998, 188, 373–386.
    68. Campbell, M.J.; Esserman, L.; Byars, N.E.; Allison, A.C.; Levy, R. Idiotype vaccination against murine B cell lymphoma. Humoral and cellular requirements for the full expression of antitumor immunity. J. Immunol. 1990, 145, 1029–1036.
    69. Dorner, B.G.; Dorner, M.B.; Zhou, X.; Opitz, C.; Mora, A.; Guttler, S.; Hutloff, A.; Mages, H.W.; Ranke, K.; Schaefer, M.; et al. Selective expression of the chemokine receptor XCR1 on cross-presenting dendritic cells determines cooperation with CD8+ T cells. Immunity 2009, 31, 823–833.
    70. Crozat, K.; Guiton, R.; Contreras, V.; Feuillet, V.; Dutertre, C.A.; Ventre, E.; Vu Manh, T.P.; Baranek, T.; Storset, A.K.; Marvel, J.; et al. The XC chemokine receptor 1 is a conserved selective marker of mammalian cells homologous to mouse CD8alpha+ dendritic cells. J. Exp. Med. 2010, 207, 1283–1292.
    71. Brown, C.C.; Gudjonson, H.; Pritykin, Y.; Deep, D.; Lavallee, V.P.; Mendoza, A.; Fromme, R.; Mazutis, L.; Ariyan, C.; Leslie, C.; et al. Transcriptional Basis of Mouse and Human Dendritic Cell Heterogeneity. Cell 2019, 179, 846–863.e24.
    72. Bosteels, C.; Fierens, K.; De Prijck, S.; Van Moorleghem, J.; Vanheerswynghels, M.; De Wolf, C.; Chalon, A.; Collignon, C.; Hammad, H.; Didierlaurent, A.M.; et al. CCR2- and Flt3-Dependent Inflammatory Conventional Type 2 Dendritic Cells Are Necessary for the Induction of Adaptive Immunity by the Human Vaccine Adjuvant System AS01. Front. Immunol. 2021, 11, 606805.
    73. Penna, G.; Vulcano, M.; Roncari, A.; Facchetti, F.; Sozzani, S.; Adorini, L. Cutting edge: Differential chemokine production by myeloid and plasmacytoid dendritic cells. J. Immunol. 2002, 169, 6673–6676.
    74. Krug, A.; Uppaluri, R.; Facchetti, F.; Dorner, B.G.; Sheehan, K.C.; Schreiber, R.D.; Cella, M.; Colonna, M. IFN-producing cells respond to CXCR3 ligands in the presence of CXCL12 and secrete inflammatory chemokines upon activation. J. Immunol. 2002, 169, 6079–6083.
    75. Megjugorac, N.J.; Young, H.A.; Amrute, S.B.; Olshalsky, S.L.; Fitzgerald-Bocarsly, P. Virally stimulated plasmacytoid dendritic cells produce chemokines and induce migration of T and NK cells. J. Leukoc. Biol. 2004, 75, 504–514.
    76. Chow, K.V.; Lew, A.M.; Sutherland, R.M.; Zhan, Y. Monocyte-Derived Dendritic Cells Promote Th Polarization, whereas Conventional Dendritic Cells Promote Th Proliferation. J. Immunol. 2016, 196, 624–636.
    77. Sutti, S.; Bruzzi, S.; Heymann, F.; Liepelt, A.; Krenkel, O.; Toscani, A.; Ramavath, N.N.; Cotella, D.; Albano, E.; Tacke, F. CX3CR1 Mediates the Development of Monocyte-Derived Dendritic Cells during Hepatic Inflammation. Cells 2019, 8, 1099.
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