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Advances in Brief |
-Type-1 Polarized Dendritic Cells
Departments of 1 Surgery, 2 Immunology, 3 Infectious Diseases and Microbiology, and 4 Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; 5 Clinical Immunotherapy Group, University of Newcastle upon Tyne, United Kingdom, 6 Departments of Cell Biology and Dermatology, University of Amsterdam, the Netherlands; and the 7 University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania
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ABSTRACT |
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 Top ABSTRACT IntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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and polyinosinic:polycytidylic acid (p-I:C) synergize with the "classical" type-1-polarizing cytokine cocktail [tumor necrosis factor (TNF)/IL-1ß/IFN
], allowing for serum-free generation of fully mature type-1-polarized DCs (DC1). Such "-type-1-polarized DC(s)" (DC1) show high migratory responses to the CCR7 ligand, 6C-kine but produce much higher levels of IL-12p70 as compared to TNF/IL-1ß/IL-6/prostaglandin E2 (PGE2)-matured DCs (sDC), the current "gold standard" in DC-based cancer vaccination. A single round of in vitro sensitization with DC1 (versus sDCs) induces up to 40-fold higher numbers of long-lived CTLs against melanoma-associated antigens: MART-1, gp100, and tyrosinase. Serum-free generation of DC1 allows, for the first time, the clinical application of DCs that combine the key three features important for their efficacy as anticancer vaccines. |
Introduction |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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during the IL-1ß/tumor necrosis factor (TNF)–induced DC maturation overcomes such maturation-associated "exhaustion," yielding stable type-1 polarized DC(s) (DC1) that produce up to 100-fold higher levels of IL-12p70 (versus control DCs) on interaction with CD40L-expressing CD4+ Th cells, and that exhibit a dramatically improved capacity to induce Th1-type responses (11)
. Here, we report that the inclusion of IFN- and polyinosinic:polycytidylic acid (p-I:C) to our original DC1-inducing cytokine cocktail, composed of IL-1ß, TNF, and IFN- (11)
, allows for the generation of DC1 in clinically relevant serum-free AIM-V medium. For the first time, this allows for the clinical use of DCs combining a fully mature status and high migratory functions with a strongly elevated, instead of exhausted, ability to produce IL-12p70. When directly compared with the current "gold standard" DCs (sDCs matured by IL-1ß/TNF/IL-6/prostaglandin E2 (PGE2); ref. 12
), such "-type-1-polarized DC" (DC1) induce up to 40-fold higher numbers of melanoma-specific CTLs in a single round of in vitro sensitization. |
Materials and Methods |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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(Intron A- IFN--2b, Schering-Plough); rhuTNF, rhuIL-1ß, and rhuIFN- (all Strathmann Biotech, Hannover, Germany); rhuIL-6 (Genzyme Cambridge, MA); lipopolysaccharide (Escherichia coli 011:B4, Sigma, St. Louis, MO); PGE2 (Sigma); and p-I:C (Sigma). To assure that endotoxin contamination did not contribute to the observed activity of p-I:C, we performed control experiments with END-X B15 endotoxin removal columns (Seikagaku America, Falmouth, MA), with no differences observed. IL-2 (gift from Chiron Corp. Emeryville, CA) and rhuIL-7 (R&D Systems, Minneapolis, MN) were used to support T-cell expansion in in vitro sensitization cultures. Flow cytometry analyses were performed with Beckman Coulter Epics XL, after labeling with CD86, CD3, CD8, CD4, CD14, CD1a, and isotype control monoclonal antibodies (all BD-PharMingen, San Jose, CA), CD83 (Coulter, Miami, FL), and CCR7 (R&D).
Generation of Dendritic Cells.
Peripheral blood mononuclear cells (PBMCs) obtained from healthy donors or melanoma patients (all stage IV, apart from a single stage-II donor) were isolated with lymphocyte separation medium (Cellgro Mediatech, Herndon, VA). Monocytes were isolated on density gradients, with Percoll (Sigma; refs. 9
, 11
) or Isolate (Irving Scientific, Santa Ana, CA), followed by plastic adherence, or with CD14+ magnetic beads (Miltenyi Biotech, Bergisch-Gladbach, Germany), in all cases with similar results. Monocytes were cultured for 6 days in 24-well plates (Falcon, Becton Dickinson Labware, Franklin Lakes, NJ) at 5 x 105 cells per well in rhu GM-CSF and IL-4 (both 1,000 IU/mL). On the basis of preliminary experiments (data not shown), we have used the following optimal concentrations of the maturation factors: IL-1ß (25 ng/mL); TNF (50 ng/mL), IFN (1,000 units/mL); IL-6 (1,000 units/mL); PGE2 (10–6 mol/L); p-I:C (20 µg/mL); IFN (3,000 units/mL); lipopolysaccharide (250 ng/mL), all added at day 6 until day 8.
Interleukin-12p70 Production.
Dendritic cells were harvested, washed, and plated in 96-well plates at 2 x 104 cells/well. To mimic the interaction with CD40L-expressing Th cells, CD40L-transfected J558 cells [a gift from Dr. P. Lane, University of Birmingham, United Kingdom, that in previous studies proved equivalent to activated CD4+ T cells and soluble CD40L (9, 10, 11
, 13)
] were added at 5 x 104 cells/well. Twenty-four-hour supernatants were analyzed by IL-12p70 ELISA (Endogen, Woburn, MA).
Chemotaxis.
Dendritic cell migration, induced by 6C-kine (Biosource, Camarillo, CA), was measured in 96-well 5 µm pore ChemoTx system (Neuro Probe, Gaithersburg, MD). DCs (25 x 103 in 25 µL of AIM-V medium) were placed on the membrane surface and incubated for 90 min at 37°C, before the enumeration of migrated DCs in bottom chambers (in four random areas). Results were expressed as mean DC numbers ± SEM in the four areas in duplicate wells. To determine the IL-12p70-producing ability of migrated DCs, CD40L-J558 cells were added directly to the bottom chambers, containing the migrated DCs, for 24 hours (see above).
CTL Induction.
CD8+ T cells (96–98% pure) from HLA-A2+ donors were negatively isolated with the StemSep system (StemCell Technologies Inc., Vancouver, British Columbia, Canada). CD8+ T cells (5 x 105 cells) were sensitized by autologous DC1 or sDC (5 x 104 cells) pulsed with the HLA-A2-restricted peptides MART-1 (27–35), gp100 (209–217 and 154–162), and tyrosinase (368–376D). 3,000 Rad -irradiated CD40L-J558 cells (5 x 104) were added as surrogate of CD40L-expressing CD4+ Th cells (9
, 11
, 13)
. In preliminary experiments, we have also used (with similar results; data not shown) the Staphylococcus Enterotoxin B (SEB)-driven model (9
, 11)
of CTL induction, with SEB-pulsed DC1 (or sDCs), CD8+ T cells, and irradiated CD4+ T cells as an alternative source of CD40L-mediated "helper signals." In all cases, rhuIL-2 (50 units/mL) and IL-7 (10 ng/mL) were added at day 4. CD8+ T-cell cultures were expanded by an additional stimulation (day 14) with irradiated peptide-pulsed autologous PBMCs. At day 28, the differentially induced CD8+ T-cell lines were stimulated with peptide-pulsed HLA-A2+ T2 cells to monitor the frequency of melanoma-specific CD8+ T cells with IFN- enzyme-linked immunospot (ELISPOT). The numbers of nonspecific spots, obtained with unpulsed T2 cells (nonspecific controls) were subtracted. CTL activity was determined by 51Cr-release assays by using T2 cells, pulsed with individual peptides, with unpulsed T2 cells as nonspecific controls.
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Results |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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and p-I:C Support the Generation of Fully Mature DC1 in Serum-free Conditions. in the maturation cocktail containing IL-1ß and TNF resulted in the development of stable type-1-polarized DC (DC1) in fetal calf serum-supplemented medium, characterized by high ability to produce IL-12p70 upon subsequent stimulation (Fig. 1)
. However, this "traditional" type-1-polarizing cocktail (IL-1ß, TNF, and IFN) was ineffective in serum-free AIM-V medium, or in human serum-supplemented medium (Fig. 1A)
. Similarly, the addition of IFN to a widely used "complete cytokine cocktail" (IL-1ß/TNF/IL-6/PGE2; ref. 12
) also proved ineffective in inducing DC1 in serum-free conditions.
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nor P-I:C alone (nor in combination with IL-1ß and TNF) were priming DCs for subsequent production of high levels of IL-12p70 (Fig. 1B
; refs. 11
, 13
), the addition of IFN to the cocktail of IL-1ß, TNF, and IFN allowed for the generation of DC1 that produced very high levels of IL-12p70 from normal donors (Fig. 1B)
and from patients with advanced melanoma (Fig. 2)
. Additional exposure to p-I:C further improved the IL-12p70-producing ability.
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-Type-1-polarized DCs (DC1), generated in serum-free conditions in the presence of all five factors (IL-1ß, TNF, IFN, IFN, and p-I:C), demonstrated a fully mature surface phenotype, similar to IL-1ß/TNF/IL-6/PGE2-matured standard DC (sDCs), expressing similar levels of the maturation-associated CD83 and CD86, and of the predictive marker of lymph-node-migratory ability of DCs, (5
, 14
, 15)
, CCR7 (Fig. 2
; please note that sDC show higher autofluorescence). The induction of a fully mature DC phenotype (DC1) was consistently observed only when the complete -type-1-polarizing cocktail, containing both IFN and p-I:C, was used (Fig. 2A)
. Interestingly, although p-I:C was inducing only incremental enhancement of the IL-12-producing function and of the expression of CD83, and CD86, it was critical for the expression of high levels of CCR7 on maturing DCs.
Type-1 DC (DC1) Combine Fully Mature Status with the Ability to Produce Elevated Levels of IL-12p70 after Migrating in Response to CCR7 Ligand.
Because PGE2, the critical component of the complete cytokine cocktail (12)
, has been shown important not only for the expression of CCR7 but also for the responsiveness of DCs to CCR7 ligands (14
, 15)
, we tested whether DC1 can migrate in response to the CCR7 ligand, 6C-kine. As shown in Fig. 2B
, DC1 efficiently (although slightly less efficient than sDCs) migrated in response to 6C-kine, indicating that IFN and p-I:C can provide an alternative (to PGE2) signal instructing DC to migrate to the lymph nodes.
Importantly, subsequent CD40L stimulation of DC1 that had migrated in response to the 6C-kine gradient, revealed the persistence of their high ability to produce IL-12p70 (Fig. 2C)
. These data demonstrate that the migratory and IL-12-producing DC functions are expressed by the same individual cells and predict high ability of DC1 to produce IL-12p70 in vivo, on migration to vaccine site-draining lymph nodes.
DC1 Show Strongly Elevated Ability to Induce Melanoma-specific CTL Responses.
To analyze the comparative ability of DC1 to promote the development of tumor antigen-specific CTLs, DC1 or sDCs were pulsed with melanoma-associated antigenic peptides and were used as an in vitro vaccine to stimulate autologous peripheral blood CD8+ T cells from HLA-A2+ melanoma patients. Long-term CD8+ T cell lines obtained by further expansion with autologous PBMCs were harvested at day 24 and were used as responder cells against HLA-A2+ T2 cells pulsed with individual peptides. As shown in Fig. 3A
, when compared with sDCs, DC1 proved superior in the induction of the melanoma-specific responses of cytotoxic T cells (CTLs). The superior activity of DC1, was evident in case of each of the HLA-A2-restricted melanoma-associated CTL epitopes (MART-1-, gp100-, and tyrosinase-specific), and was observed in each of the three melanoma patients evaluated (Fig. 3B)
, as well as in eight healthy donors (in whom MART-1-specific responses were analyzed; data not shown). Whereas sDCs were also effective in sensitizing the melanoma-specific responses, DC1 induced an average of 20-fold higher CTL levels (see the legend to Fig. 3
for the overall numbers of sDC-induced and DC1-induced CTLs).
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Discussion |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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DC1 efficiently migrate in response to 6C-kine, produce high levels of IL-12p70 after migration and subsequent CD40 ligation, and promote superior CTL induction in vitro. Although the sensitization with standard mature DCs (12)
, commonly used in current clinical trials, was also clearly effective, the data obtained with the cells from three melanoma patients (stage II-IV), indicate that one round of in vitro sensitization with DC1 yields, as an average, 20-fold higher numbers of long-lived melanoma-specific CTLs.
The present data demonstrate that DC maturation does not necessarily need to be associated with the exhaustion of their ability to produce IL-12 (9
, 10)
, and opens the possibility of clinical application of fully mature DCs with elevated IL-12-producing capacity, obviating the inclusion of either fetal calf serum (16)
or PGE2 (12)
, used in the currently available protocols. In contrast to previously applied DC-based vaccines, which relied on either immature DCs (with high ability to produce IL-12 but low stimulatory and migratory capacities) or on mature DCs (with high stimulatory and migratory functions, but reduced IL-12 production), the currently described DC1 protocol allows us for the first time to combine all of these desirable features within a single DC.
The present data show that IFN and p-I:C (an IFN-inducing factor) synergize with the IFN--based type-1-polarizing cocktails in promoting the development of fully mature DC1 under serum-free conditions. The ability of p-I:C to supplement the action of recombinant IFN suggests that its activity is partially independent from the induction of IFN/ß, in accord with observations that, in IFN/ß receptor-deficient mice, p-I:C fails to induce several maturation-associated DC markers, but does induce CCR7 (17)
. The molecular mechanism(s) of the synergism of IFN, p-I:C, and IFN in the induction of DC1, is a subject of our ongoing analysis. By analogy with other cell systems, it is likely to involve mitogen-activating protein kinase (MAPK)-, extracellular signal-regulated protein kinase (ERK)-, signal transducers and activators of transcription (STAT)-, and interferon regulatory factor (IRF)-signaling pathways (18, 19)
.
Although high IL-12p70 production plays a key role in the ability of DC1 to induce Th1 responses (8
, 11
, 13)
, other factors may be also involved. DCs matured with p-I:C alone (without IFN) show increased ability to induce polyclonal Th1 responses, in the absence of an elevated IL-12p70 production (11
, 13)
, suggesting that additional, as-yet-unidentified factors, may also contribute to high CTL-inducing ability of DC1.
The in vivo effectiveness of DC1, as prospective cancer vaccines, will need to be evaluated in comparative clinical trials. Superior CTL-inducing activity of DC1 in vitro, combined with their high in vitro migratory function (60–95% of the migratory potential of sDCs in different donors) suggests their high in vivo efficacy. However, we need to test which CD4+ T-cell antigens, including "heterologous helper antigens" such as KLH (2
, 16)
, are best suited to provide the optimal level of CD4+ T-cell help to assure the optimal performance of DC1.
In addition to their prospective use as vaccine carriers, DC1 may also be used to develop additional therapies for cancer and chronic infections with pathogens resistant to standard treatments, such as HIV. Their superior ability to activate Ag-specific T cells in vitro may also allow the use of DC1 as ex vivo inducers of tumor-specific T cells for adoptive immunotherapy, or as a tool to identify new factors and mechanisms involved in the development of type-1 immunity.
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Requests for reprints: Pawel Kalinski, University of Pittsburgh, Hillman Cancer Center, UPCI Research Pavilion, Room 1.46b, 5117 Center Avenue, Pittsburgh, PA 15213-1863. Phone: 412-623-7712; Fax: 412-623-7709; E-mail: kalinskip{at}upmc.edu
Received 4/ 8/04. Revised 5/25/04. Accepted 6/29/04.
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A. E. Morelli, J. P. Rubin, G. Erdos, O. A. Tkacheva, A. R. Mathers, A. F. Zahorchak, A. W. Thomson, L. D. Falo Jr., and A. T. Larregina CD4+ T Cell Responses Elicited by Different Subsets of Human Skin Migratory Dendritic Cells J. Immunol., December 15, 2005; 175(12): 7905 - 7915. [Abstract] [Full Text] [PDF]
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T. Dao, M. Gomez-Nunez, C. Antczak, B. Kappel, J. Singh Jaggi, T. Korontsvit, V. Zakhaleva, and D. A. Scheinberg Natural Killer Cells License Dendritic Cell Cross-Presentation of B Lymphoma Cell-Associated Antigens Clin. Cancer Res., December 15, 2005; 11(24): 8763 - 8772. [Abstract] [Full Text] [PDF]
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 J. M. Kirkwood Building Upon the Standard of Care in Adjuvant Therapy of High-Risk Melanoma J. Clin. Oncol., December 1, 2005; 23(34): 8559 - 8563. [Full Text] [PDF]
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D. A. Hokey, A. T. Larregina, G. Erdos, S. C. Watkins, and L. D. Falo Jr. Tumor Cell Loaded Type-1 Polarized Dendritic Cells Induce Th1-Mediated Tumor Immunity Cancer Res., November 1, 2005; 65(21): 10059 - 10067. [Abstract] [Full Text] [PDF]
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M. Rossi and J. W. Young Human Dendritic Cells: Potent Antigen-Presenting Cells at the Crossroads of Innate and Adaptive Immunity J. Immunol., August 1, 2005; 175(3): 1373 - 1381. [Abstract] [Full Text] [PDF]
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