Abstract
The work in our laboratory addresses two interrelated areas of dendritic cell (DC) biology: (1) the role of DCs as mediators of feedback interactions between NK cells, CD8+ and CD4+ T cells; and (2) the possibility to use such feedback and the paradigms derived from anti-viral responses, to promote the induction of therapeutic immunity against cancer. We observed that CD8+ T cells and NK cells, the classical “effector” cells, also play “helper” roles, regulating ability of DCs to induce type-1 immune immunity, critical for fighting tumors and intracellular pathogens. Our work aims to delineate which pathways of NK and CD8+ T cell activation result in their helper activity, and to identify the molecular mechanisms allowing them to induce type-1 polarized DCs (DC1s) with selectively enhanced ability to promote type-1 responses and anti-cancer immunity. The results of these studies allowed us and our colleagues to design phase I/II clinical trials incorporating the paradigms of DC polarization and helper activity of effector cells in cancer immunotherapy.
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References
Banchereau, J., Steinman RM: Dendritic cells and the control of immunity. Nature 1998;392:245–252.
Schuler G, Schuler-Thurner B, Steinman RM. The use of dendritic cells in cancer immunotherapy. Curr Opin Immunol 2003;15:138–147.
Schuler G, Steinman RM: Dendritic cells as adjuvants for immune-mediated resistance to tumors. J Exp Med 1997;186:1183–1187.
Kalinski P, Hilkens CM, Wierenga EA, Kapsenberg ML: T-cell priming by type-1 and type-2 polarized dendritic cells: the concept of a third signal. Immunol Today 1999;20:561–567.
Kapsenberg ML: Dendritic-cell control of pathogen-driven T-cell polarization. Nat Rev Immunol 2003;3:984–993.
Ikeda H, Chamoto K, Tsuji T, et al.: The critical role of type-1 innate and acquired immunity in tumor immunotherapy. Cancer Sci 2004;95:697–703.
Pulendram B: Modulating TH1/TH2 responses with mirobes, dendritic cells, and pathogen recognition receptors. Immunol Res 2004;29:187–196.
Trinchieri G: Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat Rev Immunol 2003;3:133–146.
Palucka K, Banchereau J: How dendritic cells and microbes interact to elicit or subvert protective immune responses. Curr Opin Immunol 2002;14:420–431.
Czerniecki BJ, Cohen PA, Faries M, Xu S, Roros JG, Bedrosian I: Diverse functional activity of CD83+ monocyte-derived dendritic cells and the implications for cancer vaccines. Crit Rev Immunol 2001;21:157–178.
Kalinski, P, Moser M: Consensual immunity: success-driven development of T-helper-1 and T-helper-2 responses. Nat Rev Immunol 2005;5:251–260.
Mora JR, Bono MR, Manjunath N, et al: Selective imprinting of gut-homing T cells by Peyer's patch dendritic cells. Nature 2003;424:88–93.
Mora JR, Cheng G, Picarella D, Briskin M, Buchanan N, von Andrian UH: Reciprocal and dynamic control of CD8 T cell homing by dendritic cells from skin- and gut-associated lymphoid tissues. J Exp Med 2005;201:303–316.
Mora JR, von Andrian UH: Retinoic acid: an educational “vitamin elixir” for gut-seeking T cells. Immunity 2004;21:458–460.
Schaerli P, Loetscher P, Moser B: Cutting edge: induction of follicular homing precedes effector Th cell development. J Immunol 2001;167:6082–6086.
Stagg AJ, Kamm MA, Knight SC: Intestinal dendritic cells increase T cell expression of alpha4beta7 integrin. Eur J Immunol 2002;32:1445–1454.
Weninger W, Manjunath N, von Andrian UH: Migration and differentiation of CD8+ T cells. Immunol Rev 2002;186:221–233.
Calzascia T, Masson F, Di Berardino-Besson W, et al: Homing phenotypes of tumor-specific CD8T cells are predetermined at the tumor site by crosspresenting APCs. Immunity 2005;22:175–184.
Fernandez NC, Lozier A, Flament C, et al.: Dendritic cells directly trigger NK cell functions: cross-talk relevant in innate anti-tumor immune responses in vivo. Nat Med 1999;5:405–411.
Yang L, Carbone DP: Tumor-host immune interactions and dendritic cell dysfunction. Adv Cancer Res 2004;92:13–27.
Pinzon-Charry A, Maxwell T, Lopez JA: Dendritic cell dysfunction in cancer: a mechanism for immunosuppression. Immunol Cell Biol 2005;83:451–461.
Srivastava PK: Therapeutic cancer vaccines. Curr Opin Immunol 2006;18:201–205.
Nestle FO, Farkas A, Conrad C: Dendritic-cell-based therapeutic vaccination against cancer. Curr Opin Immunol 2005;17:163–169.
Banchereau J, Palucka AK: Dendritic cells as therapeutic vaccines against cancer. Nat Rev Immunol 2005; 5:296–306.
Rosenberg SA, Yang JC, Restifo NP: Cancer immunotherapy: moving beyond current vaccines. Nat Med 2004;10:909–915.
Ruedl C, Kopf M, Bachmann MF: CD8(+) T cells mediate CD40-independent maturation of dendritic cells in vivo. J Exp Med 1999;189:1875–1884.
Gurunathan S, Stobie L, Prussin C, et al: Requirements for the maintenance of Th1 immunity in vivo following DNA vaccination: a potential immunoregulatory role for CD8+ T cells. J Immunol 2000;165:915–924.
Mailliard RB, Egawa S, Cai Q, et al: Complementary dendritic cell-activating function of CD8+ and CD4+ T cells: helper role of CD8+ T cells in the development of T helper type 1 responses. J Exp Med 2002;195:473–483.
Herberman RB, Djeu J, Kay HD, et al: natural killer cells: characteristics and regulation of activity. Immunol Rev 1979;44:43–70.
Ferlazzo G, Tsang ML, Moretta L, Melioli G, Steinman RM, Munz C: Human dendritic cells activate resting natural killer (NK) cells and are recognized via the NKp30 receptor by activated NK cells. J Exp Med 2002;195:343–351.
Gerosa F, Baldani-Guerra B, Nisii C, Marchesini V, Carra G, Trinchieri G: Reciprocal activating interaction between natural killer cells and dendritic cells. J Exp Med 2002;195:327–333.
Piccioli D, Sbrana S, Melandri E, Valiante NM: Contact-dependent stimulation and inhibition of dendritic cells by natural killer cells. J Exp Med 2002;195:335–341.
Mailliard RB, Son YI, Redlinger R, et al: Dendritic cells mediate NK cell help for Th1 and CTL responses: two-signal requirement for the induction of NK cell helper function. J Immunol 2003;171:2366–2373.
Ferlazzo G, Morandi B, D'Agostino A, et al: The interaction between NK cells and dendritic cells in bacterial infections results in rapid induction of NK cell activation and in the lysis of uninfected dendritic cells. Eur J Immunol 2003;33:306–313.
Vitale M, Chiesa MD, Carlomagno S, et al: NK-dependent DC maturation is mediated by TNF{alpha} and IFN{gamma} released upon engagement of the NKp30 triggering receptor. Blood 2005;106:566–571.
Vieira PL, de Jong EC, Wierenga EA, Kapsenberg ML, Kalinski P: Development of Th1-inducing capacity in myeloid dendritic cells requires environmental instruction. J Immunol 2000;164:4507–4512.
Kamath AT, Sheasby CE, Tough DF: Dendritic cells and NK cells stimulate bystander T cell activation in response to TLR agonists through secretion of IFN-{alpha} {beta} and IFN-{gamma}. J Immunol 2005; 174:767–776.
Gerosa F, Gobbi A, Zorzi P, et al: The reciprocal interaction of NK cells with plasmacytoid or myeloid dendritic cells profoundly affects innate resistance functions. J Immunol 2005;174:727–734.
Mailliard RB, Alber SM, Shen H, et al: IL-18-induced CD83+CCR7+ NK helper cells. J Exp Med 2005; 202:941–953.
Ferlazzo G, Pack M, Thomas D, et al: Distinct roles of IL-12 and IL-15 in human natural killer cell activation by dendritic cells from secondary lymphoid organs. Proc Natl Acad Sci USA 2004;101:16606–16611.
Cooper MA, Fehniger TA, Turner SC, et al: Human natural killer cells: a unique innate immunoregulatory role for the CD56(bright) subset. Blood 2001;97:3146–3151.
Fehniger TA, Cooper MA, Nuovo GJ, et al: CD56bright natural killer cells are present in human lymph nodes and are activated by T cell-derived IL-2: a potential new link between adaptive and innate immunity. Blood 2003; 101:3052–2057.
Ferlazzo G, Thomas D, Lin SL, et al: The abundant NK cells in human secondary lymphoid tissues require activation to express killer cell Ig-like receptors and become cytolytic. J Immunol 2004;172:1455–1462.
Carson WE, Fehniger TA, Caligiuri MA: CD56bright natural killer cell subsets: characterization of distinct functional responses to interleukin-2 and the c-kit ligand. Eur J Immunol 1997;27:354–360.
Chan CW, Crafton E, Fan HN, et al: Interferon-producing killer dendritic cells provide a link between innate and adaptive immunity. Nat Med 2006;12:207–213.
Taieb J, Chaput N, Menard C, et al: A novel dendritic cell subset involved in tumor immunosurveillance. Nat Med 2006;12:214–219.
Dhodapkar MV, Steinman RM, Sapp M, et al: Rapid generation of broad T-cell immunity in humans after a single injection of mature dendritic cells. J Clin Invest 1999;104:173–180.
de Vries IJ, Lesterhuis WJ, Scharenborg NM, et al: Maturation of dendritic cells is a prerequisite for inducing immune responses in advanced melanoma patients. Clin Cancer Res 2003;9:5091–5100.
Adema GJ, de Vries IJ, Punt CJ, Figdor CG: Migration of dendritic cell based cancer vaccines: in vivo veritas? Curr Opin Immunol 2005;17:170–174.
De Vries IJ, Krooshoop DJ, Scharenborg NM, et al: Effective migration of antigen-pulsed dendritic cells to lymph nodes in melanoma patients is determined by their maturation state. Cancer Res 2003;63:12–17.
Zitvogel L, Mayordomo JI, Tjandrawan T, et al: Therapy of murine tumors with tumor peptide-pulsed dendritic cells: dependence on T cells, B7 costimulation, and T helper cell 1-associated cytokines. J Exp Med 1996;183:87–97.
Zitvogel L, Robbins PD, Storkus WJ, et al: Interleukin-12 and B7.1 co-stimulation cooperate in the induction of effective antitumor immunity and therapy of established tumors. Eur J Immunol 1996;26:1335–1341.
Furumoto K, Arii S, Yamasaki S, et al: Spleen-derived dendritic cells engineered to enhance interleukin-12 production elicit therapeutic antitumor immune responses. Int J Cancer 2000;87:665–672.
Furumoto K, Mori A, Yamasaki S, et al: Interleukin-12-gene transduction makes DCs from tumor-bearing mice an effective inducer of tumor-specific immunity in a peritoneal dissemination model. Immunol Lett 2002;83:13–20.
Nishioka Y, Hirao M, Robbins PD, Lotze MT, Tahara H: Induction of systemic and therapeutic antitumor immunity using intratumoral injection of dendritic cells genetically modified to express interleukin 12. Cancer Res 1999;59:4035–4041.
Okada N, Iiyama S, Okada Y, et al: Immunological properties and vaccine efficacy of murine dendritic cells simultaneously expressing melanoma-associated antigen and interleukin-12. Cancer Gene Ther 2005;12:72–83.
Redlinger RE, Jr., Mailliard RB, Barksdale EM, Jr: Advanced neuroblastoma impairs dendritic cell function in adoptive immunotherapy. J Pediatr Surg 2003; 38:857–862.
Satoh Y, Esche C, Gambotto A, et al: Local administration of IL-12-transfected dendritic cells induces antitumor immune responses to colon adenocarcinoma in the liver in mice. J Exp Ther Oncol 2002;2:337–349.
Shimizu T, Berhanu A, Redlinger RE, Jr, Watkins S, Lotze MT, Barksdale EM, Jr: Interleukin-12 transduced dendritic cells induce regression of established murine neuroblastoma. J Pediatr Surg 2001;36:1285–1292.
Yamanaka R, Zullo SA, Ramsey J, et al: Marked enhancement of antitumor immune responses in mouse brain tumor models by genetically modified dendritic cells producing Semliki Forest virus-mediated interleukin-12. J Neurosurg 2002;97:611–618.
Zhang S, Zeng G, Wilkes DS, et al: Dendritic cells transfected with interleukin-12 and pulsed with tumor extract inhibit growth of murine prostatic carcinoma in vivo. Prostate 2003;55:292–298.
Kalinski P, Schuitemaker JH, Hilkens CM, Wierenga EA, Kapsenberg ML: Final maturation of dendritic cells is associated with impaired responsiveness to IFN-gamma and to bacterial IL-12 inducers: decreased ability of mature dendritic cells to produce IL-12 during the interaction with Th cells. J Immunol 1999;162:3231–3236.
Langenkamp A, Messi M, Lanzavecchia A, Sallusto F: Kinetics of dendritic cell activation: impact on priming of TH1, TH2 and nonpolarized T cells. Nat Immunol 2000;1:311–316.
Jonuleit H, Kuhn U, Muller G, et al: Pro-inflammatory cytokines and prostaglandins induce maturation of potent immunostimulatory dendritic cells under fetal calf serum-free conditions. Eur J Immunol 1997; 27:3135–3142.
Mailliard RB, Wankowicz-Kalinska A, Cai Q., et al: alpha-type-1 polarized dendritic cells: a novel immunization tool with optimized CTL-inducing activity. Cancer Res 2004;64:5934–5937.
Luft T, Jefford M, Luetjens P, et al: Functionally distinct dendritic cell (DC) populations induced by physiologic stimuli: prostaglandin E(2) regulates the migratory capacity of specific DC subsets. Blood 2002;100:1362–1372.
Scandella E, Men Y, Gillessen S, Forster R, Groettrup M: Prostaglandin E2 is a key factor for CCR7 surface expression and migration of monocyte-derived dendritic cells. Blood 2002;100:1354–1361.
Kalinski P, Schuitemaker JH, Hilkens CM, Kapsenberg ML: Prostaglandin E2 induces the final maturation of IL-12-deficient CD1a+CD83+ dendritic cells: the levels of IL-12 are determined during the final dendritic cell maturation and are resistant to further modulation. J Immunol 1998;161:2804–2809.
Kalinski P, Smits HH, Schuitemaker JH, et al: IL-4 is a mediator of IL-12p70 induction by human Th2 cells: reversal of polarized Th2 phenotype by dendritic cells. J Immunol 2000;165:1877–1881.
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Kalinski, P., Nakamura, Y., Watchmaker, P. et al. Helper roles of NK and CD8+ T cells in the induction of tumor immunity. Immunol Res 36, 137–146 (2006). https://doi.org/10.1385/IR:36:1:137
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DOI: https://doi.org/10.1385/IR:36:1:137