Abstract
As the most powerful antigen-presenting cell type, dendritic cells (DCs) can induce potent antigen-specific immune responses in vivo, hence becoming optimal cell population for vaccination purposes. DCs can be derived ex vivo in quantity and manipulated extensively to be endowed with adequate immune-stimulating capacity. After pulsing with cancer antigens in various ways, the matured DCs are administrated back into the patient. DCs home to lymphoid organs to present antigens to and activate specific lymphocytes that react to a given cancer. Ex vivo pulsed DC vaccines have been vigorously investigated for decades, registering encouraging results in relevant immunotherapeutic clinical trials, while facing some solid challenges. With more details in DC biology understood, new theory proposed, and novel technology introduced (featuring recently emerged mRNA vaccine technology), it is becoming increasingly likely that ex vivo pulsed DC vaccine will fulfill its potential in cancer immunotherapy.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Steinman RM, Cohn ZA. Identification of a novel cell type in peripheral lymphoid organs of mice. I. Morphology, quantitation, tissue distribution. J Exp Med. 1973;137:1142–62.
Collin M, Bigley V. Human dendritic cell subsets: an update. Immunology. 2018;154:3–20.
Anguille S, Smits EL, Bryant C, Van Acker HH, Goossens H, Lion E, et al. Dendritic cells as pharmacological tools for cancer immunotherapy. Pharmacol Rev. 2015;67:731–53.
Terhune J, Berk E, Czerniecki BJ. Dendritic cell-induced Th1 and Th17 cell differentiation for cancer therapy. Vaccines. 2013;1:527–49.
Leal Rojas IM, Mok WH, Pearson FE, Minoda Y, Kenna TJ, Barnard RT, et al. Human blood CD1c+ dendritic cells promote Th1 and Th17 effector function in memory CD4+ T cells. Front Immunol. 2017;8:971.
Chow KV, Lew AM, Sutherland RM, Zhan Y. Monocyte-derived dendritic cells promote Th polarization, whereas conventional dendritic cells promote Th proliferation. J Immunol. 2016;196:624–36.
Thomas R, Yang X. NK-DC crosstalk in immunity to microbial infection. J Immunol Res. 2016;2016:7.
Unal A, Birekul A, Unal C, Karakus E, Köker Y. Dendritic cell production from allogeneic donor CD34+ stem cells and mononuclear cells; cancer vaccine. Blood. 2016;128:5723.
Plantinga M, de Haar CG, Dünnebach E. van den Beemt DAMH, Bloemenkamp KWM, Mokry M, et al. Cord-blood-stem-cell-derived conventional dendritic cells specifically originate from CD115-expressing precursors. Cancers. 2019;11:pii: E181.
Romani N, Gruner S, Brang D, Kämpgen E, Lenz A, Trockenbacher B, et al. Proliferating dendritic cell progenitors in human blood. J Exp Med. 1994;180:83–93.
Sallusto F, Lanzavecchia A. Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colonystimulating factor plus interleukin 4 and downregulated by tumor necrosis factor alpha. J Exp Med. 1994;179:1109–18.
Romani N, Reider D, Heuer M, Ebner S, Kämpgen E, Eibl B, et al. Generation of mature dendritic cells from human blood An improved method with special regard to clinical applicability. J Immunol Methods. 1996;196:137–51.
Zhou LJ, Tedder TF. CD14+ blood monocytes can differentiate into functionally mature CD83+ dendritic cells. Proc Natl Acad Sci U S A. 1996;93:2588–92.
Van Acker HH, Anguille S, De Reu H, Berneman ZN, Smits EL, Van Tendeloo VF, et al. Interleukin-15-cultured dendritic cells enhance anti-tumor gamma delta T cell functions through IL-15 secretion. Front Immunol. 2018;9:658.
Versteven M. Abstract B137: preclinical evaluation of a Wilms’ tumor protein 1-targeted interleukin-15 dendritic cell vaccine: T-cell activity and batch production. Cancer Immunol Res. 2019;7:B137.
Mohty M, Mohty M, Vialle-Castellano A, Nunes JA, Isnardon D, Olive D, et al. IFN-alpha skews monocyte differentiation into Toll-like receptor 7-expressing dendritic cells with potent functional activities. J Immunol. 2003;171:3385–93.
Brabants E, Heyns K, De Smet S, Devreker P, Ingels J, De Cabooter N, et al. An accelerated, clinical-grade protocol to generate high yields of type 1-polarizing messenger RNA–loaded dendritic cells for cancer vaccination. Cytotherapy. 2018;20:1164–81.
Jonuleit H, Kühn U, Müller G, Steinbrink K, Paragnik L, Schmitt E, et al. Pro-inflammatory cytokines and prostaglandins induce maturation of potent immunostimulatory dendritic cells under fetal calf serum-free conditions. Eur J Immunol. 1997;27:3135–42.
Vopenkova K, Mollova K, Buresova I, Michalek J. Complex evaluation of human monocyte-derived dendritic cells for cancer immunotherapy. J Cell Mol Med. 2012;16:2827–37.
Massa C, Thomas C, Wang E, Marincola F, Seliger B. Different maturation cocktails provide dendritic cells with different chemoattractive properties. J Transl Med. 2015;13:175.
Shinde P, Melinkeri S, Santra MK, Kale V, Limaye L. Autologous hematopoietic stem cells are a preferred source to generate dendritic cells for immunotherapy in multiple myeloma patients. Front Immunol. 2019;10:1079.
Bernhard H, Disis ML, Heimfeld S, Hand S, Gralow JR, Cheever MA, et al. Generation of immunostimulatory dendritic cells from human CD34+ hematopoietic progenitor cells of the bone marrow and peripheral blood. Cancer Res. 1995;55:1099–104.
Bontkes HJ, De Gruijl TD, Schuurhuis GJ, Scheper RJ, Meijer CJ, Hooijberg E, et al. Expansion of dendritic cell precursors from human CD34+ progenitor cells isolated from healthy donor blood; growth factor combination determines proliferation rate and functional outcome. J Leukoc Biol. 2002;72:321–9.
Kirkling ME, Cytlak U, Lau CM, Lewis KL, Resteu A, Khodadadi-Jamayran A, et al. Notch signaling facilitates in vitro generation of cross-presenting classical dendritic cells. Cell Rep. 2018;23:3658–72. e3656.
Helft J, Anjos-Afonso F, van der Veen AG, Chakravarty P, Bonnet D, Reis e Sousa C, et al. Dendritic cell lineage potential in human early hematopoietic progenitors. Cell Rep. 2017;20:529–37.
Rosa FF, Pires CF, Kurochkin I, Ferreira AG, Gomes AM, Palma LG, et al. Direct reprogramming of fibroblasts into antigen-presenting dendritic cells. Sci Immunol. 2018;3:pii: eaau4292.
Senju S, Haruta M, Matsumura K, Matsunaga Y, Fukushima S, Ikeda T, et al. Generation of dendritic cells and macrophages from human induced pluripotent stem cells aiming at cell therapy. Gene Ther. 2011;18:874–83.
Horton C, Davies TJ, Lahiri P, Sachamitr P, Fairchild PJ. Induced pluripotent stem cells reprogrammed from primary dendritic cells provide an abundant source of immunostimulatory dendritic cells for use in immunotherapy. Stem Cells. 2020;38:67–79.
Leone DA, Rees AJ, Kain R. Dendritic cells and routing cargo into exosomes. Immunol Cell Biol. 2018;96:683–93.
Saxena M, Bhardwaj N. Re-emergence of dendritic cell vaccines for cancer treatment. Trends Cancer. 2018;4:119–37.
Bol KF, Schreibelt G, Rabold K, Wculek SK, Schwarze JK, Dzionek A, et al. The clinical application of cancer immunotherapy based on naturally circulating dendritic cells. J Immunother Cancer. 2019;7:109.
Gross S, Erdmann M, Haendle I, Voland S, Berger T, Schultz E, et al. Twelve-year survival and immune correlates in dendritic cell-vaccinated melanoma patients. JCI Insight. 2017;2:e91438.
Mastelic-Gavillet B, Balint K, Boudousquie C, Gannon PO, Kandalaft LE. Personalized dendritic cell vaccines-recent breakthroughs and encouraging clinical results. Front Immunol. 2019;10:766.
Kukutsch NA, Roßner S, Austyn JM, Schuler G, Lutz MB. Formation and kinetics of MHC class I-ovalbumin peptide complexes on immature and mature murine dendritic cells. J Investig Dermatol. 2000;115:449–53.
Zhang H, Tang K, Zhang Y, Ma R, Ma J, Li Y, et al. Cell-free tumor microparticle vaccines stimulate dendritic cells via cGAS/STING signaling. Cancer Immunol Res. 2015;3:196–205.
Gu X, Erb U, Büchler MW, Zöller M. Improved vaccine efficacy of tumor exosome compared to tumor lysate loaded dendritic cells in mice. Int J Cancer. 2015;136:E74–84.
Anguille S, Smits EL, Lion E, van Tendeloo VF, Berneman ZN. Clinical use of dendritic cells for cancer therapy. Lancet Oncol. 2014;15:e257–67.
Liau LM, Ashkan K, Tran DD, Campian JL, Trusheim JE, Cobbs CS, et al. First results on survival from a large Phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma. J Transl Med. 2018;16:142. Erratum in: J Transl Med. 2018;16:179.
Carreno BM, Magrini V, Becker-Hapak M, Kaabinejadian S, Hundal J, Petti AA, et al. Cancer immunotherapy. A dendritic cell vaccine increases the breadth and diversity of melanoma neoantigen-specific T cells. Science. 2015;348:803–8.
Mitchell DA, Batich KA, Gunn MD, Huang MN, Sanchez-Perez L, Nair SK, et al. Tetanus toxoid and CCL3 improve dendritic cell vaccines in mice and glioblastoma patients. Nature. 2015;519:366–9.
Banchereau J, Palucka AK, Dhodapkar M, Burkeholder S, Taquet N, Rolland A, et al. Immune and clinical responses in patients with metastatic melanoma to CD34+ progenitor-derived dendritic cell vaccine. Cancer Res. 2001;61:6451–8.
Schreibelt G, Bol KF, Westdorp H, Wimmers F, Aarntzen EH. Duiveman-de Boer T, et al. Effective clinical responses in metastatic melanoma patients after vaccination with primary myeloid dendritic cells. Clin Cancer Res. 2016;22:2155–66.
Hsu JL, Bryant CE, Papadimitrious MS, Kong B, Gasiorowski RE, Orellana D, et al. A blood dendritic cell vaccine for acute myeloid leukemia expands antitumor T cell responses at remission. Oncoimmunology. 2018;7:e1419114.
Wculek SK, Cueto FJ, Mujal AM, Melero I, Krummel MF, Sancho D, et al. Dendritic cells in cancer immunology and immunotherapy. Nat Rev Immunol. 2020;20:7–24.
Rauch S, Lutz J, Kowalczyk A, Schlake T, Heidenreich R. RNActive(R) technology: generation and testing of stable and immunogenic mRNA vaccines. Methods Mol Biol. 2017;1499:89–107.
Iavarone C, O’Hagan DT, Yu D, Delahaye NF, Ulmer JB. Mechanism of action of mRNA-based vaccines. Expert Rev Vaccines. 2017;16:871–81.
Van Lint S, Heirman C, Thielemans K, Breckpot K. mRNA: from a chemical blueprint for protein production to an off-the-shelf therapeutic. Hum Vaccine Immunother. 2013;9:265–74.
Schlake T, Thess A, Fotin-Mleczek M, Kallen KJ. Developing mRNA-vaccine technologies. RNA Biol. 2012;9:1319–30.
Asrani KH, Farelli JD, Stahley MR, Miller RL, Cheng CJ, Subramanian RR, et al. Optimization of mRNA untranslated regions for improved expression of therapeutic mRNA. RNA Biol. 2018;15:756–62.
Zlotorynski E. The short tail that wags the mRNA. Nat Rev Mol Cell Biol. 2017;19:2–3.
Holtkamp S, Kreiter S, Selmi A, Simon P, Koslowski M, Huber C, et al. Modification of antigen-encoding RNA increases stability, translational efficacy, and T-cell stimulatory capacity of dendritic cells. Blood. 2006;108:4009–17.
Galaine J, Borg C, Godet Y, Adotévi O. Interest of tumor-specific CD4 T Helper 1 cells for therapeutic anticancer vaccine. Vaccines. 2015;3:490–502.
Bonehill A, Heirman C, Tuyaerts S, Michiels A, Breckpot K, Brasseur F, et al. Messenger RNA-electroporated dendritic cells presenting MAGE-A3 simultaneously in HLA class I and class II molecules. J Immunol. 2004;172:6649–57.
Aarntzen EH, Schreibelt G, Bol K, Lesterhuis WJ, Croockewit AJ, de Wilt JH, et al. Vaccination with mRNA-electroporated dendritic cells induces robust tumor antigen-specific CD4+ and CD8+ T cells responses in stage III and IV melanoma patients. Clin Cancer Res. 2012;18:5460–70.
Bonehill A, Tuyaerts S, Van Nuffel AM, Heirman C, Bos TJ, Fostier K, et al. Enhancing the T-cell stimulatory capacity of human dendritic cells by coelectroporation with CD40L, CD70 and constitutively active TLR4 encoding mRNA. Mol Ther. 2008;16:1170–80.
Neyns B. A phase I clinical trial on the combined intravenous (IV) and intradermal (ID) administration of autologous TriMix-DC cellular therapy in patients with pretreated melanoma (TriMixIDIV). J Clin Oncol. 2011;29:2519.
Wilgenhof S, Van Nuffel AM, Benteyn D, Corthals J, Aerts C, Heirman C, et al. A phase IB study on intravenous synthetic mRNA electroporated dendritic cell immunotherapy in pretreated advanced melanoma patients. Ann Oncol. 2013;24:2686–93.
Boczkowski D, Nair SK, Snyder D, Gilboa E. Dendritic cells pulsed with RNA are potent antigen-presenting cells in vitro and in vivo. J Exp Med. 1996;184:465–72.
Diken M, Kreiter S, Selmi A, Britten CM, Huber C, Türeci Ö, et al. Selective uptake of naked vaccine RNA by dendritic cells is driven by macropinocytosis and abrogated upon DC maturation. Gene Ther. 2011;18:702–8.
Kranz LM, Diken M, Haas H, Kreiter S, Loquai C, Reuter KC, et al. Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy. Nature. 2016;534:396–401.
Diebold SS, Kaisho T, Hemmi H, Akira S. Reis e Sousa C. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science. 2004;303:1529–31.
Gerer KF, Hoyer S, Dorrie J, Schaft N. Electroporation of mRNA as universal technology platform to transfect a variety of primary cells with antigens and functional proteins. Methods Mol Biol. 2017;1499:165–78.
Van Nuffel AM, Corthals J, Neyns B, Heirman C, Thielemans K, Bonehill A, et al. Immunotherapy of cancer with dendritic cells loaded with tumor antigens and activated through mRNA electroporation. Methods Mol Biol. 2010;629:405–52.
Dewitte H, Van Lint S, Heirman C, Thielemans K, De Smedt SC, Breckpot K, et al. The potential of antigen and TriMix sonoporation using mRNA-loaded microbubbles for ultrasound-triggered cancer immunotherapy. J Control Release. 2014;194:28–36.
McCullough KC, Bassi I, Milona P, Suter R, Thomann-Harwood L, Englezou P, et al. Self-replicating replicon-RNA delivery to dendritic cells by chitosannanoparticles for translation in vitro and in vivo. Mol Ther Nucleic acids. 2014;3:e173.
Chung DJ, Carvajal RD, Postow MA, Sharma S, Pronschinske KB, Shyer JA, et al. Langerhans-type dendritic cells electroporated with TRP-2 mRNA stimulate cellular immunity against melanoma: results of a phase I vaccine trial. Oncoimmunology. 2017;7:e1372081.
Wilgenhof S, Corthals J, Heirman C, van Baren N, Lucas S, Kvistborg P, et al. Phase II study of autologous monocyte-derived mRNA electroporated dendritic cells (TriMixDC-MEL) plus Ipilimumab in patients with pretreated advanced melanoma. J Clin Oncol. 2016;34:1330–8.
Almand B, Resser JR, Lindman B, Nadaf S, Clark JI, Kwon ED, et al. Clinical significance of defective dendritic cell differentiation in cancer. Clin Cancer Res. 2000;6:1755–66.
Ramos RN, Chin LS, Dos Santos AP, Bergami-Santos PC, Laginha F, Barbuto JA, et al. Monocyte-derived dendritic cells from breast cancer patients are biased to induce CD4+CD25+Foxp3+ regulatory T cells. J Leukoc Biol. 2012;92:673–82.
Celli S, Day M, Müller AJ, Molina-Paris C, Lythe G, Bousso P. How many dendritic cells are required to initiate a T-cell response? Blood. 2012;120:3945–8.
van Heijst JW, Gerlach C, Swart E, Sie D, Nunes-Alves C, Kerkhoven RM, et al. Recruitment of antigen-specific CD8+ T cells in response to infection is markedly efficient. Science. 2009;325:1265–9.
Segura E, Touzot M, Bohineust A, Cappuccio A, Chiocchia G, Hosmalin A, et al. Human inflammatory dendritic cells induce Th17 cell differentiation. Immunity. 2013;38:336–48.
Xu Y, Zhan Y, Lew AM, Naik SH, Kershaw MH. Differential development of murine dendritic cells by GM-CSF versus Flt3 ligand has implications for inflammation and trafficking. J Immunol. 2007;179:7577–84.
Hespel C, Moser M. Role of inflammatory dendritic cells in innate and adaptive immunity. Eur J Immunol. 2012;42:2535–43.
Allan RS, Waithman J, Bedoui S, Jones CM, Villadangos JA, Zhan Y, et al. Migratory dendritic cells transfer antigen to a lymph node-resident dendritic cell population for efficient CTL priming. Immunity. 2006;25:153–62.
Gurevich I, Feferman T, Milo I, Tal O, Golani O, Drexler I, et al. Active dissemination of cellular antigens by DCs facilitates CD8+ T-cell priming in lymph nodes. Eur J Immunol. 2017;47:1802–18.
Garg AD, Coulie PG, Van den Eynde BJ, Agostinis P. Integrating next-generation dendritic cell vaccines into the current cancer immunotherapy landscape. Trends Immunol. 2017;38:577–93.
Palucka K, Banchereau J, Mellman I. Designing vaccines based on biology of human dendritic cell subsets. Immunity. 2010;33:464–78.
Huang MN, Nicholson LT, Batich KA, Swartz AM, Kopin D, Wellford S, et al. Antigen-loaded monocyte administration induces potent therapeutic antitumor T cell responses. J Clin Invest. 2020;130:774–88.
Reinhard K, Rengstl B, Oehm P, Michel K, Billmeier A, Hayduk N, et al. An RNA vaccine drives expansion and efficacy of claudin-CAR-T cells against solid tumors. Science. 2020;367:446–53.
Richner JM, Himansu S, Dowd KA, Butler SL, Salazar V, Fox JM, et al. Modified mRNA vaccines protect against Zika virus infection. Cell. 2017;169:176.
RodrÃguez-Ruiz ME, Perez-Gracia JL, RodrÃguez I, Alfaro C, Oñate C, Pérez G, et al. Combined immunotherapy encompassing intratumoral poly-ICLC, dendritic-cell vaccination and radiotherapy in advanced cancer patients. Ann Oncol. 2018;29:1312–9.
Nowicki TS, Berent-Maoz B, Cheung-Lau G, Huang RR, Wang X, Tsoi J, et al. A pilot trial of the combination of transgenic NY-ESO-1-reactive adoptive cellular therapy with dendritic cell vaccination with or without Ipilimumab. Clin Cancer Res. 2019;25:2096–108.
Vo MC, Jung SH, Chu TH, Lee HJ, Lakshmi TJ, Park HS, et al. Lenalidomide and programmed death-1 blockade synergistically enhances the effects of dendritic cell vaccination in a model of murine myeloma. Front Immunol. 2018;9:1370.
Hirooka Y, Kawashima H, Ohno E, Ishikawa T, Kamigaki T, Goto S, et al. Comprehensive immunotherapy combined with intratumoral injection of zoledronate-pulsed dendritic cells, intravenous adoptive activated T lymphocyte and gemcitabine in unresectable locally advanced pancreatic carcinoma: a phase I/II trial. Oncotarget. 2018;9:2838–47.
Soliman H, Khambati F, Han HS, Ismail-Khan R, Bui MM, Sullivan DM, et al. A phase-1/2 study of adenovirus-p53 transduced dendritic cell vaccine in combination with indoximod in metastatic solid tumors and invasive breast cancer. Oncotarget. 2018;9:10110–7.
Molla KA, Yang Y. CRISPR/Cas-mediated base editing: technical considerations and practical applications. Trends Biotechnol. 2019;37:1121–42.
Acknowledgements
This work was supported by the National Natural Science Foundation of China (81872821) and the National Key S&T Special Projects (2018ZX09201018-024).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Rights and permissions
About this article
Cite this article
Gu, Yz., Zhao, X. & Song, Xr. Ex vivo pulsed dendritic cell vaccination against cancer. Acta Pharmacol Sin 41, 959–969 (2020). https://doi.org/10.1038/s41401-020-0415-5
Received:
Accepted:
Published:
Version of record:
Issue date:
DOI: https://doi.org/10.1038/s41401-020-0415-5
Keywords
This article is cited by
-
Innovative combinatory approaches with dendritic cell-based vaccines: bridging preclinical insights and clinical challenges
Clinical and Experimental Medicine (2026)
-
Innovative gene engineering and drug delivery systems for dendritic cells in cancer immunotherapy
Journal of Biomedical Science (2025)
-
Oncolytic virus encoding 4-1BBL and IL15 enhances the efficacy of tumor-infiltrating lymphocyte adoptive therapy in HCC
Cancer Gene Therapy (2025)
-
The role of dendritic cells in recurrent pregnancy loss
Immunologic Research (2025)
-
Cross-talk between cuproptosis and ferroptosis to identify immune landscape in cervical cancer for mRNA vaccines development
European Journal of Medical Research (2024)
