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Molecular Signatures of Maturing Dendritic Cells Jin et al. Journal of Translational Medicine 2010, 8:4 http://www.translational-medicine.com/content/8/1/4 RESEARCH Open Access Molecular signatures of maturing dendritic cells: implications for testing the quality of dendritic cell therapies Ping Jin1*†, Tae Hee Han1,2†, Jiaqiang Ren1, Stefanie Saunders1, Ena Wang1, Francesco M Marincola1, David F Stroncek1 Abstract Background: Dendritic cells (DCs) are often produced by granulocyte-macrophage colony-stimulating factor (GM- CSF) and interleukin-4 (IL-4) stimulation of monocytes. To improve the effectiveness of DC adoptive immune cancer therapy, many different agents have been used to mature DCs. We analyzed the kinetics of DC maturation by lipopolysaccharide (LPS) and interferon-g (IFN-g) induction in order to characterize the usefulness of mature DCs (mDCs) for immune therapy and to identify biomarkers for assessing the quality of mDCs. Methods: Peripheral blood mononuclear cells were collected from 6 healthy subjects by apheresis, monocytes were isolated by elutriation, and immature DCs (iDCs) were produced by 3 days of culture with GM-CSF and IL-4. The iDCs were sampled after 4, 8 and 24 hours in culture with LPS and IFN-g and were then assessed by flow cytometry, ELISA, and global gene and microRNA (miRNA) expression analysis. Results: After 24 hours of LPS and IFN-g stimulation, DC surface expression of CD80, CD83, CD86, and HLA Class II antigens were up-regulated. Th1 attractant genes such as CXCL9, CXCL10, CXCL11 and CCL5 were up-regulated during maturation but not Treg attractants such as CCL22 and CXCL12. The expression of classical mDC biomarker genes CD83, CCR7, CCL5, CCL8, SOD2, MT2A, OASL, GBP1 and HES4 were up-regulated throughout maturation while MTIB, MTIE, MTIG, MTIH, GADD45A and LAMP3 were only up-regulated late in maturation. The expression of miR-155 was up-regulated 8-fold in mDCs. Conclusion: DCs, matured with LPS and IFN-g, were characterized by increased levels of Th1 attractants as opposed to Treg attractants and may be particularly effective for adoptive immune cancer therapy. Introduction monocytes are usually used to produce mDC in vitro by Dendritic cells (DC) are key players in both innate and culture with growth factors and cytokines [6,7]. adaptive immune responses. They are potent antigen pre- Large quantities of mononuclear cells can easily be senting cells that recognize, process, and present antigens collected from the peripheral blood by leukapheresis. to T-cells in vivo [1-3]. Consequently, DC-based immu- Monocytes can be isolated from other leukocytes col- notherapy has become one of the most promising lected by apheresis with high purity by adherence, elu- approaches for the treatment of cancer [4,5]. The fre- triation, or using immunomagnetic beads [8-10]. To quency of DCs in the peripheral blood is naturally low produce immature DCs (iDCs), monocytes are usually and they are difficult to separate from other peripheral incubated with granulocyte-macrophage colony-stimu- blood leukocytes [6], therefore, to enhance DC function, lating factor (GM-CSF) and interleukin-4 (IL-4). Because hematopoietic progenitor cells or peripheral blood mature DCs (mDCs) are superior to iDCs for the stimu- lation of cytotoxic T-cells, iDCs derived from monocytes are often treated with various exogenous stimuli known * Correspondence: [email protected] to induce DCs maturation including lipopolysaccharide † Contributed equally 1Department of Transfusion Medicine, Clinical Center, National Institutes of (LPS) and interferon-g (IFN-g) [5,11]. One of the goals Health, Bethesda, Maryland, USA © 2010 Jin et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Jin et al. Journal of Translational Medicine 2010, 8:4 Page 2 of 15 http://www.translational-medicine.com/content/8/1/4 of this study was to characterize the molecular profile of Deerfield, IL) from 6 healthy donors in the Depart- changes associated with LPS and IFN-g induced DC ment of Transfusion Medicine (DTM), Clinical Center, maturation to estimate the effectiveness of these mDCs National Institutes of Health (NIH). All donors signed in adoptive immune cancer therapy. an informed consent approved by a NIH Institutional When developing cellular therapies such as mDCs it is Review Board. Monocytes were isolated from the often necessary to compare products manufactured with PBMC concentrates on the day of PBMC collection by a standard method and an alternative method. It is also elutriation (Elutra®, Gambro BCT, Lakewood, CO) necessary to determine if products manufactured from using the instrument’s automatic mode according to the starting material of different people are consistent the manufacturer’s recommendations. The monocytes or similar. Once the manufacturing process has been were treated with GM-CSF (2000 IU/mL, R&D Sys- established and clinical products are being manufac- tems, Minneapolis, MN) and IL-4 (2000 IU/mL, R&D tured, clinical cellular therapies must also be assessed Systems) for 3 days to produce iDCs. The iDCs were for potency. Another goal of this study was to identify then treated for 24 hours with LPS and IFN-g to pro- molecular biomarkers that were associated with DC duce mDCs. The results of analysis of iDCs and mDCs maturation and in order to characterize mDCs and that by flow cytometry and gene expression profiling have could be used for consistency, comparibility, and been previously published [12]. potency testing. DCs are often assessed by flow cytometry for the DC preparation, maturation, and harvest expression of the costimulatory molecules CD80 and The elutriated monocytes from each donor were sus- CD86, the maturation marker CD83, the chemokine pended at 6.7 × 106/mL with RPMI 1640 (Invitrogen, receptor CCR7, and antigen presentation molecules, Carlsbad, CA) supplemented with 10% fetal calf serum HLA class II antigens, to document the transition of (FSC) (Invitrogen), 2 mM L-glutamine (Invitrogen), 1% iDCs to mDCs. Some cellular therapy laboratories nonessential amino acids (Invitrogen), 1% pyruvate also test the function of DCs by measuring their abil- (Invitrogen), 100 units/mL penicillin/streptomycin (Invi- ity to produce IL-12, IL-10, IL-23 or IFN-g following trogen), and 50 μM 2-mercaptoethanol (Sigma, St stimulation. However, the diverse functions of DC Louis, MO). A total of 10 mL of monocyte suspension therapies indicate that additional biomarkers are was cultured in T25 culture flasks (Nalge Nunc Interna- necessory to characterize mDCs. Based on the multi- tional, Rochester, NY) overnight in a humidified incuba- ple functions of DCs and their broad spectrum of tor with 5% CO2 at 37°C. On Day 1, 2000 IU/mL effector molecules, it is highly improbable that a lim- human IL-4 (R&D Systems) and 2000 IU/mL GM-CSF ited number of biomarkers can adequately measure (R&D Systems) were added to the culture. On Day 3, DC potency. But whole transcriptome expression ana- an additional 2000 IU/mL IL-4 and GM-CSF were lysis and microRNA (miR) profiling analysis of the added. To induce DC maturation, on day 4, 100 ng/mL DC maturation process could provide better insight LPS (Sigma) and 1000 IU/mL IFN-g (R&D Systems) into DC biology and identify biomarkers that are indi- were added. The DCs were harvested at 0, 4, 8 and 24 cators of DC potency. hours (h) after the addition of LPS and IFN-g.To Although monocytes, iDCs, and mDCs have been remove the adherent DCs, 2 mM EDTA-PBS was added characterized at a molecular level, few studies have com- to each flask on ice. The harvested cells were pelleted, prehensively studied the molecular events associated washed twice with HBSS, and resuspended in RPMI with DC maturation. In this study we compared the 1640. The total number of cells harvested and their via- kinetics of global changes of both gene and miR expres- bility was measured microscopically after adding Trypan sion associated with LPS and IFN-g induced DC matura- Blue. tion. Gene and miR changes in DCs were assessed after 4, 8 and 24 hours of LPS and IFN-g stimulation. To vali- Flow cytometeric analysis date the functional activity of DCs, we also tested solu- The purity of the elutriated monocytes was evaluated by ble protein production in culture supernatant after 24 flow cytometry using CD14-PE,CD19-FITC,CD3-PE- hours of maturation and after incubation with CD40 Cy5, and CD56-APC (Becton Dickinson, Mountain ligand transfected mouse fibroblasts. View, CA) and isotype controls (Becton Dickinson). To confirm the maturation of the DCs, the harvested DCs Materials and methods were tested with CD80-FITC, CD83-PE, CD86-FITC, Study design HLA-DR-PE-Cy5, and CD14-APC (Becton Dickinson) Peripheral blood mononuclear cell (PBMC) concen- and isotype controls (Becton Dickson). Flow cytometry trates were collected using a CS3000 Plus blood cell acquisition and analysis were performed with a FACS- separator (Baxter Healthcare Corp., Fenwal Division, can using CellQuest software (Becton Dickinson). Jin et al. Journal of Translational Medicine 2010, 8:4 Page 3 of 15 http://www.translational-medicine.com/content/8/1/4 Analysis of DC function and cytokine generation consisting of 827 human, mouse, rat and virus probes To measure DC cytokine production, iDC and mDCs plus two control probes. The probes were 5’ amine (100,000 cells/ml) were co-incubated with 50,000 cells/ modified and printed in duplicate in the Immunoge- ml of adherent mouse fibroblasts transfected to express netics Section of the DTM on CodeLink activated slides human CD40-Ligand (CD40L-LTK) in 48-well plates. (General Electric, GE Health, NJ, USA) via covalent This cell line was kindly provided by Dr.
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