The molecular identification of human cancer antigens has allowed the development of antigen-specific immunotherapy. In one approach, autologous antigen-specific T cells are expanded ex vivo and then re-infused into patients. Another approach is through vaccination; that is, the provision of an antigen together with an adjuvant to elicit therapeutic T cells in vivo. Cancer vaccines aim to induce tumour-specific effector T cells that can reduce the tumour mass and to induce tumour-specific memory T cells that can control tumour relapse.
Owing to their properties, dendritic cells (DCs) are often called 'nature's adjuvants' and thus have become the natural targets for antigen delivery. DCs provide an essential link between the innate and the adaptive immune responses. DCs are at the centre of the immune system owing to their ability to control both tolerance and immune responses. These key properties of DCs render them the central candidates for antigen delivery and vaccination, including therapeutic vaccination against cancer.
The immune system has the potential to eliminate neoplastic cells. However, tumour cells alone are poor antigen-presenting cells (APCs). Studies with mouse models demonstrate that the generation of protective anti-tumour immune responses depends on the presentation of tumour antigens by DCs. When compared with other APCs, such as macrophages, DCs are extremely efficient at antigen presentation and inducing T cell immunity, thus explaining their nickname of 'professional APCs'.
Mice and humans have distinct functional subsets of DCs that generate different types of immune response. DCs are also able to mature; that is, to acquire novel functions following microbe encounters. Under steady state conditions, DCs in peripheral tissues are 'immature'. These immature DCs induce tolerance either through T cell deletion or through inducing the expansion of regulatory and/or suppressor T cells. DCs promptly respond to environmental signals and differentiate into mature DCs that can efficiently launch immune responses. It is now accepted that the adjuvant component of vaccines primarily acts by triggering DC maturation.
DCs are important targets for therapeutic interventions in cancer. Two themes of research are growing: first, how cancer cells alter DC physiology; and second, how we can build on the powerful properties of DCs to generate novel cancer immunotherapies (including vaccines).
Cancer immunotherapy attempts to harness the power and specificity of the immune system to treat tumours. The molecular identification of human cancer-specific antigens has allowed the development of antigen-specific immunotherapy. In one approach, autologous antigen-specific T cells are expanded ex vivo and then re-infused into patients. Another approach is through vaccination; that is, the provision of an antigen together with an adjuvant to elicit therapeutic T cells in vivo. Owing to their properties, dendritic cells (DCs) are often called 'nature's adjuvants' and thus have become the natural agents for antigen delivery. After four decades of research, it is now clear that DCs are at the centre of the immune system owing to their ability to control both immune tolerance and immunity. Thus, DCs are an essential target in efforts to generate therapeutic immunity against cancer.
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Darnell, R. B. Onconeural antigens and the paraneoplastic neurologic disorders: at the intersection of cancer, immunity, and the brain. Proc. Natl Acad. Sci. USA 93, 4529–4536 (1996).
Albert, M. L. et al. Tumor-specific killer cells in paraneoplastic cerebellar degeneration. Nature Med. 4, 1321–1324 (1998).
Diamond, M. S. et al. Type I interferon is selectively required by dendritic cells for immune rejection of tumors. J. Exp. Med. 208, 1989–2003 (2011).
Fuertes, M. B. et al. Host type I IFN signals are required for antitumor CD8+ T cell responses through CD8α+ dendritic cells. J. Exp. Med. 208, 2005–2016 (2011). References 3 and 4 demonstrate that DCs are essential for the generation of anti-tumour immunity in vivo.
Banchereau, J. & Steinman, R. M. Dendritic cells and the control of immunity. Nature 392, 245–252 (1998).
Steinman, R. M. & Banchereau, J. Taking dendritic cells into medicine. Nature 449, 419–426 (2007). References 5 and 6 are outstanding reviews that cover a decade of research on DCs starting from basic biology and moving onto pathophysiology and medicine.
Steinman, R. M. Decisions about dendritic cells: past, present, and future. Annu. Rev. Immunol. 17 Nov 2011 [epub ahead of print].
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. 137, 1142–1162 (1973).
Steinman, R. M. & Cohn, Z. A. in Mononuclear Phagocytes in Immunity, Infection, and Pathology (ed. van Furth, R.) 95–109 (Blackwell Scientific Publications Ltd., Oxford, 1975).
Shortman, K. & Naik, S. H. Steady-state and inflammatory dendritic-cell development. Nature Rev. Immunol. 7, 19–30 (2007).
Shortman, K. & Heath, W. R. The CD8+ dendritic cell subset. Immunol. Rev. 234, 18–31 (2010).
Hashimoto, D., Miller, J. & Merad, M. Dendritic cell and macrophage heterogeneity in vivo. Immunity 35, 323–335 (2011).
Liu, K. & Nussenzweig, M. C. Origin and development of dendritic cells. Immunol. Rev. 234, 45–54 (2010). An outstanding review summarizing the development of DCs and the identification of transcription factors that are specific to DC lineage
Trombetta, E. S. & Mellman, I. Cell biology of antigen processing in vitro and in vivo. Annu. Rev. Immunol. 23, 975–1028 (2005). An outstanding review that summarizes the principles of antigen capture, processing and presentation by DCs.
Banchereau, J. et al. Immunobiology of dendritic cells. Annu. Rev. Immunol. 18, 767–811 (2000).
Itano, A. A. & Jenkins, M. K. Antigen presentation to naive CD4 T cells in the lymph node. Nature Immunol. 4, 733–739 (2003).
Albert, M. L. & Bhardwaj, N. Resurrecting the dead: DCs cross-present antigen derived from apoptotic cells on MHC I. Immunologist 6, 194–198 (1998).
Albert, M. L. et al. Immature dendritic cells phagocytose apoptotic cells via αvβ5 and CD36, and cross-present antigens to cytotoxic T lymphocytes. J. Exp. Med. 188, 1359–1368 (1998).
Heath, W. R. & Carbone, F. R. Cross-presentation, dendritic cells, tolerance and immunity. Annu. Rev. Immunol. 19, 47–64 (2001).
Jego, G., Pascual, V., Palucka, A. K. & Banchereau, J. Dendritic cells control B cell growth and differentiation. Curr. Dir. Autoimmun. 8, 124–139 (2005).
Qi, H., Egen, J. G., Huang, A. Y. & Germain, R. N. Extrafollicular activation of lymph node B cells by antigen-bearing dendritic cells. Science 312, 1672–1676 (2006).
Batista, F. D. & Harwood, N. E. The who, how and where of antigen presentation to B cells. Nature Rev. Immunol. 9, 15–27 (2009).
Bergtold, A., Desai, D. D., Gavhane, A. & Clynes, R. Cell surface recycling of internalized antigen permits dendritic cell priming of B cells. Immunity 23, 503–514 (2005).
Steinman, R. M., Hawiger, D. & Nussenzweig, M. C. Tolerogenic dendritic cells. Annu. Rev. Immunol. 21, 685–711 (2003). This review describes the principles of tolerance induction by DCs.
Caux, C. et al. Activation of human dendritic cells through CD40 cross-linking. J. Exp. Med. 180, 1263–1272 (1994).
Fujii, S., Liu, K., Smith, C., Bonito, A. J. & Steinman, R. M. The linkage of innate to adaptive immunity via maturing dendritic cells in vivo requires CD40 ligation in addition to antigen presentation and CD80/86 costimulation. J. Exp. Med. 199, 1607–1618 (2004).
Pulendran, B., Palucka, K. & Banchereau, J. Sensing pathogens and tuning immune responses. Science 293, 253–256 (2001).
Palucka, A. K. & Banchereau, J. How dendritic cells and microbes interact to elicit or subvert protective immune responses. Curr. Opin. Immunol. 14, 420–431 (2002).
Ueno, H. et al. Harnessing human dendritic cell subsets for medicine. Immunol. Rev. 234, 199–212 (2010).
Cheng, P., Zhou, J. & Gabrilovich, D. Regulation of dendritic cell differentiation and function by Notch and Wnt pathways. Immunol. Rev. 234, 105–119 (2010).
Maldonado-Lopez, R. et al. CD8α+ and CD8α- subclasses of dendritic cells direct the development of distinct T helper cells in vivo. J. Exp. Med. 189, 587–592 (1999).
Pulendran, B. et al. Distinct dendritic cell subsets differentially regulate the class of immune response in vivo. Proc. Natl Acad. Sci. USA 96, 1036–1041 (1999). References 31 and 32 demonstrate for the first time that distinct subsets of DCs induce different types of immune responses in vivo.
Kool, M. et al. Cutting edge: alum adjuvant stimulates inflammatory dendritic cells through activation of the NALP3 inflammasome. J. Immunol. 181, 3755–3759 (2008).
Flach, T. L. et al. Alum interaction with dendritic cell membrane lipids is essential for its adjuvanticity. Nature Med. 17, 479–487 (2011).
Pascual, V., Chaussabel, D. & Banchereau, J. A genomic approach to human autoimmune diseases. Annu. Rev. Immunol. 28, 535–571 (2010).
Chevrier, N. et al. Systematic Discovery of TLR signaling components delineates viral-sensing circuits. Cell 147, 853–867 (2011).
Dzionek, A. et al. BDCA-2, BDCA-3, and BDCA-4: three markers for distinct subsets of dendritic cells in human peripheral blood. J. Immunol. 165, 6037–6046 (2000).
Siegal, F. P. et al. The nature of the principal type 1 interferon-producing cells in human blood. Science 284, 1835–1837 (1999).
Di Pucchio, T. et al. Direct proteasome-independent cross-presentation of viral antigen by plasmacytoid dendritic cells on major histocompatibility complex class I. Nature Immunol. 9, 551–557 (2008).
Jego, G. et al. Plasmacytoid dendritic cells induce plasma cell differentiation through type I interferon and interleukin 6. Immunity 19, 225–234 (2003).
Shaw, J., Wang, Y. H., Ito, T., Arima, K. & Liu, Y. J. Plasmacytoid dendritic cells regulate B-cell growth and differentiation via CD70. Blood 115, 3051–3057 (2010).
Liu, Y. J. IPC: professional type 1 interferon-producing cells and plasmacytoid dendritic cell precursors. Annu. Rev. Immunol. 23, 275–306 (2005). An outstanding summary of the biology of pDCs and the production of type I interferon family members.
Bachem, A. et al. Superior antigen cross-presentation and XCR1 expression define human CD11c+CD141+ cells as homologues of mouse CD8+ dendritic cells. J. Exp. Med. 207, 1273–1281 (2010).
Crozat, K. et al. The XC chemokine receptor 1 is a conserved selective marker of mammalian cells homologous to mouse CD8α+ dendritic cells. J. Exp. Med. 207, 1283–1292 (2010).
Klechevsky, E. et al. Functional specializations of human epidermal Langerhans cells and CD14+ dermal dendritic cells. Immunity 29, 497–510 (2008).
Valladeau, J. & Saeland, S. Cutaneous dendritic cells. Semin. Immunol. 17, 273–283 (2005).
Nestle, F. O., Zheng, X. G., Thompson, C. B., Turka, L. A. & Nickoloff, B. J. Characterization of dermal dendritic cells obtained from normal human skin reveals phenotypic and functionally distinctive subsets. J. Immunol. 151, 6535–6545 (1993).
Caux, C. et al. CD34+ hematopoietic progenitors from human cord blood differentiate along two independent dendritic cell pathways in response to granulocyte-macrophage colony-stimulating factor plus tumor necrosis factor α: II. Functional analysis. Blood 90, 1458–1470 (1997). The concept and the first demonstration of distinct subsets of human DCs eliciting different types of T cell immunity in vitro are presented.
Ueno, H. et al. Dendritic cell subsets in health and disease. Immunol. Rev. 219, 118–142 (2007).
Cheong, C. et al. Microbial stimulation fully differentiates monocytes to DC-SIGN/CD209+ dendritic cells for immune T cell areas. Cell 143, 416–429 (2010).
Romani, N. et al. Proliferating dendritic cell progenitors in human blood. J. Exp. Med. 180, 83–93 (1994).
Paquette, R. L. et al. Interferon-α and granulocyte-macrophage colony-stimulating factor differentiate peripheral blood monocytes into potent antigen-presenting cells. J. Leukoc. Biol. 64, 358–367 (1998).
Chomarat, P., Dantin, C., Bennett, L., Banchereau, J. & Palucka, A. K. TNF skews monocyte differentiation from macrophages to dendritic cells. J. Immunol. 171, 2262–2269 (2003).
Mohamadzadeh, M. et al. Interleukin 15 skews monocyte differentiation into dendritic cells with features of Langerhans cells. J. Exp. Med. 194, 1013–1020 (2001).
Levings, M. K. et al. Differentiation of Tr1 cells by immature dendritic cells requires IL-10 but not CD25+CD4+ Tr cells. Blood 105, 1162–1169 (2005).
Zapata-Gonzalez, F. et al. 9-cis-Retinoic acid (9cRA), a retinoid X receptor (RXR) ligand, exerts immunosuppressive effects on dendritic cells by RXR-dependent activation: inhibition of peroxisome proliferator-activated receptor γ blocks some of the 9cRA activities, and precludes them to mature phenotype development. J. Immunol. 178, 6130–6139 (2007).
Penna, G. & Adorini, L. 1 α, 25-dihydroxyvitamin D3 inhibits differentiation, maturation, activation, and survival of dendritic cells leading to impaired alloreactive T cell activation. J. Immunol. 164, 2405–2411 (2000).
Jiang, A. et al. Disruption of E-cadherin-mediated adhesion induces a functionally distinct pathway of dendritic cell maturation. Immunity 27, 610–624 (2007).
Zhang, Z. et al. The helicase DDX41 senses intracellular DNA mediated by the adaptor STING in dendritic cells. Nature Immunol. 12, 959–965 (2011).
Manicassamy, S. & Pulendran, B. Modulation of adaptive immunity with Toll-like receptors. Semin. Immunol. 21, 185–193 (2009).
Takeuchi, O. & Akira, S. Pattern recognition receptors and inflammation. Cell 140, 805–820 (2010). An outstanding review that focuses on how phagocytes recognize microbes.
Reis e Sousa, C. Dendritic cells in a mature age. Nature Rev. Immunol. 6, 476–483 (2006).
Sancho, D. et al. Identification of a dendritic cell receptor that couples sensing of necrosis to immunity. Nature 458, 899–903 (2009). The first identification of a DC receptor that is involved in the recognition of necrotic cells; the engagement of this receptor leads to the generation of immunity.
Dudziak, D. et al. Differential antigen processing by dendritic cell subsets in vivo. Science 315, 107–111 (2007). Targeting distinct subsets of DCs in vivo with specific antibodies generated distinct types of T cell responses through distinct antigen-processing pathways.
Tesniere, A. et al. Immunogenic cancer cell death: a key-lock paradigm. Curr. Opin. Immunol. 20, 504–511 (2008). This paper discusses how different types of cell death, including those induced by chemotherapy, might induce anti-tumour immunity.
Davis, I. D., Jefford, M., Parente, P. & Cebon, J. Rational approaches to human cancer immunotherapy. J. Leukoc. Biol. 73, 3–29 (2003).
Dunne, A., Marshall, N. A. & Mills, K. H. TLR based therapeutics. Curr. Opin. Pharmacol. 11, 404–411 (2011).
Barrat, F. J. et al. Nucleic acids of mammalian origin can act as endogenous ligands for Toll-like receptors and may promote systemic lupus erythematosus. J. Exp. Med. 202, 1131–1139 (2005).
Zhang, Z. et al. DDX1, DDX21, and DHX36 helicases form a complex with the adaptor molecule TRIF to sense dsRNA in dendritic cells. Immunity 34, 866–878 (2011).
Dhodapkar, M. V., Dhodapkar, K. M. & Palucka, A. K. Interactions of tumor cells with dendritic cells: balancing immunity and tolerance. Cell Death Differ. 15, 39–50 (2008).
Ravichandran, K. S. Beginnings of a good apoptotic meal: the find-me and eat-me signaling pathways. Immunity 35, 445–455 (2011). An outstanding review on the recognition of apoptotic cells by phagocytes.
Chao, M. P. et al. Anti-CD47 antibody synergizes with rituximab to promote phagocytosis and eradicate non-Hodgkin lymphoma. Cell 142, 699–713 (2010).
Chomarat, P., Banchereau, J., Davoust, J. & Palucka, A. K. IL-6 switches the differentiation of monocytes from dendritic cells to macrophages. Nature Immunol. 1, 510–514 (2000).
Hiltbold, E. M., Vlad, A. M., Ciborowski, P., Watkins, S. C. & Finn, O. J. The mechanism of unresponsiveness to circulating tumor antigen MUC1 is a block in intracellular sorting and processing by dendritic cells [In Process. Citation]. J. Immunol. 165, 3730–3741 (2000).
Fiorentino, D. F. et al. IL-10 acts on the antigen-presenting cell to inhibit cytokine production by Th1 cells. J. Immunol. 146, 3444–3451 (1991).
Steinbrink, K., Wolfl, M., Jonuleit, H., Knop, J. & Enk, A. H. Induction of tolerance by IL-10-treated dendritic cells. J. Immunol. 159, 4772–4780 (1997).
Aspord, C. et al. Breast cancer instructs dendritic cells to prime interleukin 13-secreting CD4+ T cells that facilitate tumor development. J. Exp. Med. 204, 1037–1047 (2007).
De Monte, L. et al. Intratumor T helper type 2 cell infiltrate correlates with cancer-associated fibroblast thymic stromal lymphopoietin production and reduced survival in pancreatic cancer. J. Exp. Med. 208, 469–478 (2011).
DeNardo, D. G. et al. CD4+ T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages. Cancer Cell 16, 91–102 (2009).
Cao, W. et al. Regulation of TLR7/9 responses in plasmacytoid dendritic cells by BST2 and ILT7 receptor interaction. J. Exp. Med. 206, 1603–1614 (2009).
Treilleux, I. et al. Dendritic cell infiltration and prognosis of early stage breast cancer. Clin. Cancer Res. 10, 7466–7474 (2004).
Kukreja, A. et al. Enhancement of clonogenicity of human multiple myeloma by dendritic cells. J. Exp. Med. 203, 1859–1865 (2006).
Bahlis, N. J. et al. CD28-mediated regulation of multiple myeloma cell proliferation and survival. Blood 109, 5002–5010 (2007).
Coukos, G., Benencia, F., Buckanovich, R. J. & Conejo-Garcia, J. R. The role of dendritic cell precursors in tumour vasculogenesis. Br. J. Cancer 92, 1182–1187 (2005).
Curiel, T. J. et al. Dendritic cell subsets differentially regulate angiogenesis in human ovarian cancer. Cancer Res. 64, 5535–5538 (2004).
Heslop, H. E., Brenner, M. K. & Rooney, C. M. Donor T cells to treat EBV-associated lymphoma. N. Engl. J. Med. 331, 679–680 (1994).
Yee, C. et al. Adoptive T cell therapy using antigen-specific CD8+ T cell clones for the treatment of patients with metastatic melanoma: in vivo persistence, migration, and antitumor effect of transferred T cells. Proc. Natl Acad. Sci. USA 99, 16168–16173 (2002).
Dudley, M. E. et al. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 298, 850–854 (2002).
Appay, V., Douek, D. C. & Price, D. A. CD8+ T cell efficacy in vaccination and disease. Nature Med. 14, 623–628 (2008). An outstanding review that discusses the key features and requirements for effective anti-tumour CD8+ T cell-mediated immune responses.
Araki, K., Youngblood, B. & Ahmed, R. The role of mTOR in memory CD8 T-cell differentiation. Immunol. Rev. 235, 234–243 (2010).
Zhang, N. & Bevan, M. J. CD8+ T cells: foot soldiers of the immune system. Immunity 35, 161–168 (2011). An outstanding review that discusses the key features of CD8+ T cell-mediated immune responses.
Bousso, P. & Robey, E. Dynamics of CD8+ T cell priming by dendritic cells in intact lymph nodes. Nature Immunol. 4, 579–585 (2003).
Chen, L. et al. Costimulation of antitumor immunity by the B7 counterreceptor for the T lymphocyte molecules CD28 and CTLA-4. Cell 71, 1093–1102 (1992).
Shuford, W. W. et al. 4–1BB costimulatory signals preferentially induce CD8+ T cell proliferation and lead to the amplification in vivo of cytotoxic T cell responses. J. Exp. Med. 186, 47–55 (1997).
Waldmann, T. A. The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design. Nature Rev. Immunol. 6, 595–601 (2006).
Pardoll, D. M. & Topalian, S. L. The role of CD4+ T cell responses in antitumor immunity. Curr. Opin. Immunol. 10, 588–594 (1998).
Antony, P. A. et al. CD8+ T cell immunity against a tumor/self-antigen Is augmented by CD4+ T helper cells and hindered by naturally occurring T regulatory cells. J. Immunol. 174, 2591–2601 (2005).
Sun, J. C. & Bevan, M. J. Defective CD8 T cell memory following acute infection without CD4 T cell help. Science 300, 339–342 (2003).
Corthay, A. et al. Primary antitumor immune response mediated by CD4+ T cells. Immunity 22, 371–383 (2005).
Quezada, S. A. et al. Tumor-reactive CD4+ T cells develop cytotoxic activity and eradicate large established melanoma after transfer into lymphopenic hosts. J. Exp. Med. 207, 637–650 (2010).
Le Floc'h, A. et al. α E β 7 integrin interaction with E-cadherin promotes antitumor CTL activity by triggering lytic granule polarization and exocytosis. J. Exp. Med. 204, 559–570 (2007).
Roncarolo, M. G., Bacchetta, R., Bordignon, C., Narula, S. & Levings, M. K. Type 1 T regulatory cells. Immunol. Rev. 182, 68–79 (2001).
Fukaura, H. et al. Induction of circulating myelin basic protein and proteolipid protein-specific transforming growth factor-β1-secreting Th3 T cells by oral administration of myelin in multiple sclerosis patients. J. Clin. Invest. 98, 70–77 (1996).
Kastenmuller, W. et al. Regulatory T cells selectively control CD8+ T cell effector pool size via IL-2 restriction. J. Immunol. 187, 3186–3197 (2011).
Sasaki, K., Pardee, A. D., Okada, H. & Storkus, W. J. IL-4 inhibits VLA-4 expression on Tc1 cells resulting in poor tumor infiltration and reduced therapy benefit. Eur. J. Immunol. 38, 2865–2873 (2008).
Harlin, H. et al. Chemokine expression in melanoma metastases associated with CD8+ T-cell recruitment. Cancer Res. 69, 3077–3085 (2009).
Vianello, F. et al. Murine B16 melanomas expressing high levels of the chemokine stromal-derived factor-1/CXCL12 induce tumor-specific T cell chemorepulsion and escape from immune control. J. Immunol. 176, 2902–2914 (2006).
Gabrilovich, D. I. & Nagaraj, S. Myeloid-derived suppressor cells as regulators of the immune system. Nature Rev. Immunol. 9, 162–174 (2009).
Menetrier-Caux, C., Gobert, M. & Caux, C. Differences in tumor regulatory T-cell localization and activation status impact patient outcome. Cancer Res. 69, 7895–7898 (2009).
Higano, C. S. et al. Integrated data from 2 randomized, double-blind, placebo-controlled, phase 3 trials of active cellular immunotherapy with sipuleucel-T in advanced prostate cancer. Cancer 115, 3670–3679 (2009).
Kantoff, P. W. et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N. Engl. J. Med. 363, 411–422 (2010).
Schwartzentruber, D. J. et al. A phase III multi-institutional randomized study of immunization with the gp100:209–217 (210M) peptide followed by high-dose IL-2 compared with high-dose IL-2 alone in patients with metastatic melanoma. J. Clin. Oncol. Abstr. 27, CRA9011 (2009).
Schuster, S. J. et al. Idiotype vaccine therapy (BiovaxID) in follicular lymphoma in first complete remission: phase III clinical trial results. J. Clin. Oncol. Abstr. 27, 2 (2009).
Kantoff, P. W. et al. Overall survival analysis of a phase II randomized controlled trial of a poxviral-based PSA-targeted immunotherapy in metastatic castration-resistant prostate cancer. J. Clin. Oncol. 28, 1099–1105 (2010).
Palucka, K., Ueno, H., Roberts, L., Fay, J. & Banchereau, J. Dendritic cells: are they clinically relevant? Cancer J. 16, 318–324 (2010).
Draube, A. et al. Dendritic cell based tumor vaccination in prostate and renal cell cancer: a systematic review and meta-analysis. PLoS ONE 6, e18801 (2011).
Gilboa, E. The makings of a tumor rejection antigen. Immunity 11, 263–270 (1999).
Parmiani, G., De Filippo, A., Novellino, L. & Castelli, C. Unique human tumor antigens: immunobiology and use in clinical trials. J. Immunol. 178, 1975–1979 (2007).
Boon, T., Coulie, P. G., Van den Eynde, B. J. & van der Bruggen, P. Human T cell responses against melanoma. Annu. Rev. Immunol. 24, 175–208 (2006). References 117–119 discuss the issue of tumour antigenicity.
Finn, O. Cancer Immunology. N. Engl. J. Med. 358, 2704–2715 (2008).
Finn, O. J. Cancer vaccines: between the idea and the reality. Nature Rev. Immunol. 3, 630–641 (2003).
Bonifaz, L. et al. Efficient targeting of protein antigen to the dendritic cell receptor DEC-205 in the steady state leads to antigen presentation on major histocompatibility complex class I products and peripheral CD8+ T cell tolerance. J. Exp. Med. 196, 1627–1638 (2002).
Bonifaz, L. C. et al. In vivo targeting of antigens to maturing dendritic cells via the DEC-205 receptor improves T cell vaccination. J. Exp. Med. 199, 815–824 (2004).
Hawiger, D. et al. Dendritic cells induce peripheral T cell unresponsiveness under steady state conditions in vivo. J. Exp. Med. 194, 769–780 (2001). References 122–124 describe the seminal work demonstrating DC targeting in vivo with specific antibodies that target DC surface receptors and the consequences on T cell-mediated immune responses.
Soares, H. et al. A subset of dendritic cells induces CD4+ T cells to produce IFN-γ by an IL-12-independent but CD70-dependent mechanism in vivo. J. Exp. Med. 204, 1095–1106 (2007).
Li, D. et al. Targeting self- and foreign antigens to dendritic cells via DC-ASGPR generates IL-10-producing suppressive CD4+ T cells. J. Exp. Med. 209, 109–121 (2012).
Schlom, J., Gulley, J. L. & Arlen, P. M. Paradigm shifts in cancer vaccine therapy. Exp. Biol. Med. 233, 522–534 (2008).
Hoos, A. et al. Improved endpoints for cancer immunotherapy trials. J. Natl Cancer Inst. 102, 1388–1397 (2010).
Hodi, F. S. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723 (2010).
Paczesny, S. et al. Expansion of melanoma-specific cytolytic CD8+ T cell precursors in patients with metastatic melanoma vaccinated with CD34+ progenitor-derived dendritic cells. J. Exp. Med. 199, 1503–1511 (2004).
Welters, M. J. et al. Success or failure of vaccination for HPV16-positive vulvar lesions correlates with kinetics and phenotype of induced T-cell responses. Proc. Natl Acad. Sci. USA 107, 11895–11899 (2010).
Gaucher, D. et al. Yellow fever vaccine induces integrated multilineage and polyfunctional immune responses. J. Exp. Med. 205, 3119–3131 (2008).
Querec, T. D. et al. Systems biology approach predicts immunogenicity of the yellow fever vaccine in humans. Nature Immunol. 10, 116–125 (2009).
Pulendran, B., Li, S. & Nakaya, H. I. Systems vaccinology. Immunity 33, 516–529 (2010).
Greenberg, P. D. Ralph M. Steinman: a man, a microscope, a cell, and so much more. Proc. Natl Acad. Sci. USA 108, 20871–20872 (2011).
Topalian, S. L., Weiner, G. J. & Pardoll, D. M. Cancer Immunotherapy comes of age. J. Clin. Oncol. 29, 4828–4836 (2011).
Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011). An outstanding review that summarizes current concepts of cancer biology and for the first time incorporates inflammation and immune evasion into the paradigm of cancer–host interactions.
Zitvogel, L. et al. Immunogenic tumor cell death for optimal anticancer therapy: the calreticulin exposure pathway. Clin. Cancer Res. 16, 3100–3104 (2010).
Ma, Y. et al. How to improve the immunogenicity of chemotherapy and radiotherapy. Cancer Metastasis Rev. 30, 71–82 (2011).
Taylor, C. et al. Augmented HER-2 specific immunity during treatment with trastuzumab and chemotherapy. Clin. Cancer Res. 13, 5133–5143 (2007).
Mitsunaga, M. et al. Cancer cell-selective in vivo near infrared photoimmunotherapy targeting specific membrane molecules. Nature Med. 17, 1685–1691 (2011).
Moore, K. W., de Waal Malefyt, R., Coffman, R. L. & O'Garra, A. Interleukin-10 and the interleukin-10 receptor. Annu. Rev. Immunol. 19, 683–765 (2001).
Terabe, M. et al. NKT cell-mediated repression of tumor immunosurveillance by IL-13 and the IL-4R-STAT6 pathway. Nature Immunol. 1, 515–520 (2000).
Li, M. O., Wan, Y. Y., Sanjabi, S., Robertson, A. K. & Flavell, R. A. Transforming growth factor-β regulation of immune responses. Annu. Rev. Immunol. 24, 99–146 (2005).
Terabe, M. et al. Synergistic enhancement of CD8+ T cell-mediated tumor vaccine efficacy by an anti-transforming growth factor-β monoclonal antibody. Clin. Cancer Res. 15, 6560–6569 (2009).
Peggs, K. S., Quezada, S. A., Korman, A. J. & Allison, J. P. Principles and use of anti-CTLA4 antibody in human cancer immunotherapy. Curr. Opin. Immunol. 18, 206–213 (2006).
Peggs, K. S., Quezada, S. A., Chambers, C. A., Korman, A. J. & Allison, J. P. Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti-CTLA-4 antibodies. J. Exp. Med. 206, 1717–1725 (2009).
Iwai, Y. et al. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc. Natl Acad. Sci. USA 99, 12293–12297 (2002).
Gajewski, T. F. Failure at the effector phase: immune barriers at the level of the melanoma tumor microenvironment. Clin. Cancer Res. 13, 5256–5261 (2007).
Hamanishi, J. et al. Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proc. Natl Acad. Sci. USA 104, 3360–3365 (2007).
Gabrilovich, D. Mechanisms and functional significance of tumour-induced dendritic-cell defects. Nature Rev. Immunol. 4, 941–952 (2004).
Rabinovich, G. A., Gabrilovich, D. & Sotomayor, E. M. Immunosuppressive strategies that are mediated by tumor cells. Annu. Rev. Immunol. 25, 267–296 (2007).
Watts, T. H. TNF/TNFR family members in costimulation of T cell responses. Annu. Rev. Immunol. 23, 23–68 (2005).
Maus, M. V. et al. Ex vivo expansion of polyclonal and antigen-specific cytotoxic T lymphocytes by artificial APCs expressing ligands for the T-cell receptor, CD28 and 4–1BB. Nature Biotech. 20, 143–148 (2002).
Watanabe, N. et al. Hassall's corpuscles instruct dendritic cells to induce CD4+CD25+ regulatory T cells in human thymus. Nature 436, 1181–1185 (2005).
Manicassamy, S. et al. Activation of β-catenin in dendritic cells regulates immunity versus tolerance in the intestine. Science 329, 849–853 (2010).
Murphy, G., Tjoa, B., Ragde, H., Kenny, G. & Boynton, A. Phase I clinical trial: T-cell therapy for prostate cancer using autologous dendritic cells pulsed with HLA-A0201-specific peptides from prostate-specific membrane antigen. Prostate 29, 371–380 (1996).
Nestle, F. O. et al. Vaccination of melanoma patients with peptide- or tumor lysate-pulsed dendritic cells. Nature Med. 4, 328–332 (1998).
Holtl, L. et al. Cellular and humoral immune responses in patients with metastatic renal cell carcinoma after vaccination with antigen pulsed dendritic cells. J. Urol. 161, 777–782 (1999).
Yu, J. S. et al. Vaccination of malignant glioma patients with peptide-pulsed dendritic cells elicits systemic cytotoxicity and intracranial T-cell infiltration. Cancer Res. 61, 842–847 (2001).
Reichardt, V. L. et al. Idiotype vaccination using dendritic cells after autologous peripheral blood stem cell transplantation for multiple myeloma: a feasibility study. Blood 93, 2411–2419 (1999).
Timmerman, J. M. et al. Idiotype-pulsed dendritic cell vaccination for B-cell lymphoma: clinical and immune responses in 35 patients. Blood 99, 1517–1526 (2002).
Thurner, B. et al. Vaccination with Mage-3A1 peptide-pulsed mature, monocyte-derived dendritic cells expands specific cytotoxic T cells and induces regression of some metastases in advanced stage IV melanoma. J. Exp. Med. 190, 1669–1678 (1999).
Mackensen, A. et al. Phase I study in melanoma patients of a vaccine with peptide-pulsed dendritic cells generated in vitro from CD34+ hematopoietic progenitor cells. Int. J. Cancer 86, 385–392 (2000).
Banchereau, J. et al. Immune and clinical responses in patients with metastatic melanoma to CD34+ progenitor-derived dendritic cell vaccine. Cancer Res. 61, 6451–6458 (2001).
Fong, L. et al. Altered peptide ligand vaccination with Flt3 ligand expanded dendritic cells for tumor immunotherapy. Proc. Natl Acad. Sci. USA 98, 8809–8814 (2001).
Dhodapkar, M. V., Steinman, R. M., Krasovsky, J., Munz, C. & Bhardwaj, N. Antigen-specific inhibition of effector T cell function in humans after injection of immature dendritic cells. J. Exp. Med. 193, 233–238 (2001).
Geiger, J. D. et al. Vaccination of pediatric solid tumor patients with tumor lysate-pulsed dendritic cells can expand specific T cells and mediate tumor regression. Cancer Res. 61, 8513–8519 (2001).
Schuler-Thurner, B. et al. Rapid induction of tumor-specific type 1 T helper cells in metastatic melanoma patients by vaccination with mature, cryopreserved, peptide-loaded monocyte-derived dendritic cells. J. Exp. Med. 195, 1279–1288 (2002).
Nair, S. K. et al. Induction of tumor-specific cytotoxic T lymphocytes in cancer patients by autologous tumor RNA-transfected dendritic cells. Ann. Surg. 235, 540–549 (2002).
Palucka, A. K. et al. Dendritic cells loaded with killed allogeneic melanoma cells can induce objective clinical responses and MART-1 specific CD8+ T-cell immunity. J. Immunother. 29, 545–557 (2006).
Salcedo, M. et al. Vaccination of melanoma patients using dendritic cells loaded with an allogeneic tumor cell lysate. Cancer Immunol. Immunother. 55, 819–829 (2006).
Chang, D. H. et al. Sustained expansion of NKT cells and antigen-specific T cells after injection of α-galactosyl-ceramide loaded mature dendritic cells in cancer patients. J. Exp. Med. 201, 1503–1517 (2005).
Aarntzen, E. H. et al. Early identification of antigen-specific immune responses in vivo by [18F]-labeled 3′-fluoro-3′-deoxy-thymidine ([18F]FLT) PET imaging. Proc. Natl Acad. Sci. USA 108, 18396–18399 (2011).
Lesterhuis, W. J. et al. Route of administration modulates the induction of dendritic cell vaccine-induced antigen-specific T cells in advanced melanoma patients. Clin. Cancer Res. 17, 5725–5735 (2011).
Romano, E. et al. Peptide-loaded Langerhans cells, despite increased IL15 secretion and T-cell activation in vitro, elicit antitumor T-cell responses comparable to peptide-loaded monocyte-derived dendritic cells in vivo. Clin. Cancer Res. 17, 1984–1997 (2011).
Okada, H. et al. Induction of CD8+ T-cell responses against novel glioma-associated antigen peptides and clinical activity by vaccinations with α-type 1 polarized dendritic cells and polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose in patients with recurrent malignant glioma. J. Clin. Oncol. 29, 330–336 (2011).
We dedicate this Review to our long-time friend and colleague, Ralph M. Steinman, who compelled many of us to study dendritic cells and their role in disease pathophysiology and medicine. We thank all of the patients and volunteers who participated in our studies and clinical trials. We thank former and current members of the Baylor Institute for Immunology Research for their contributions to their progress. Our studies have been supported by the US National Institutes of Health (P01 CA084514, U19 AIO57234, R01 CA089440, CA078846 and CA140602), the Dana Foundation, the Susan Komen Foundation, the Baylor Health Care System; the Baylor Health Care System Foundation, the ANRS and the INSERM. K.P. holds the Michael A. Ramsay Chair for Cancer Immunology Research. Owing to space limits we could cite only a small proportion of the vast number of publications.
K.P. has a collaborative project and grant support from Roche. J.B. is an employee of Roche.
- Innate immune system
Comprises the cells and molecules that defend the host from infection by other organisms in a nonspecific manner. That is, cells of the innate immune system recognize and respond to pathogens in a generic way and, unlike the adaptive immune system, do not confer immune memory.
- Adaptive immune system
The part of the immune system that is mediated by antigen-specific lymphocytes and antibodies; it is highly antigen-specific and includes the development of immunological memory.
- Paraneoplastic diseases
Neurological diseases induced as a result of tumour burden; generally caused by the release of tumour-derived hormones, peptides and/or cytokines, or by the misguided destruction of normal tissue by immune cells targeted against malignant cells. Most commonly present with cancers of the lung, breast, ovaries or lymphatic system (lymphoma).
- CD8+ T cell
A subgroup of T lymphocytes that recognize their targets by binding to antigen that is associated with major histocompatibility class I molecules, which are present on the surface of nearly every cell. They can give rise to cytotoxic T lymphocytes, which can kill virally infected cells and tumour cells.
- Antigen-presenting cells
(APCs). Cells that display foreign antigen complexes with major histocompatibility complex molecules to T cells.
An agent mixed with an antigen that enhances the immune response to that antigen on vaccination.
Specialized monocyte-derived phagocytic cells that can capture and degrade invading microbes.
- Afferent lymphatics
Vessels that enter the periphery of the lymph node and bring cells and particles from the tissue to the lymph node.
- CD4+ T cells
Also known as helper T cells. A subgroup of T lymphocytes that regulate other immune cells and that are essential in B cell antibody class switching, as well as in the activation and growth of cytotoxic T cells. These cells recognize antigen that is associated with major histocompatibility complex class II molecules.
- Regulatory T (TReg) cells
A subset of CD4+ T cells that maintain self-tolerance. They can express high levels of CD25 and the forkhead transcription factor FOXP3. They can secrete cytokines, such as IL-10 and TGFβ, which inhibit other T cells.
- Natural killer (NK) cells
Innate immune system lymphocytes that are able to kill virally infected cells and tumour cells, particularly cells that lack the expression of major histocompatibility complex class I molecules (the presence of which inhibits NK cell cytotoxicity).
White blood cells that are able to ingest foreign particles, microbes and dying cells.
- Mast cells
Tissue-resident cells that contain histamine and heparin-rich granules and that mediate allergy and anaphylaxis. They are also important in the defence against pathogens.
- Humoral immunity
A component of the adaptive immune system that is mediated by secreted antibodies. Antibodies are secreted from B cells that have differentiated into plasma cells.
- Opsonizing antibodies
A subclass of antibodies that can bind to a pathogen or particle and at the same time bind to an Fc receptor on a phagocyte, thereby facilitating phagocytosis and pathogen clearance.
Individual antigenic determinants from the variable regions of the immunoglobulin heavy and light chains are referred to as idiotopes; the sum of the individual idiotopes is referred to as the idiotype.
- Memory T cells
A subgroup of antigen-specific T cells that persist long after an infection has resolved. They quickly expand to large numbers of effector T cells on re-exposure to cognate antigen, thus providing immunological 'memory'.
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Palucka, K., Banchereau, J. Cancer immunotherapy via dendritic cells. Nat Rev Cancer 12, 265–277 (2012). https://doi.org/10.1038/nrc3258
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