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Cancer Immunology, Immunotherapy
Published in: Cancer Immunology, Immunotherapy 5/2010

01-05-2010 | Original Article

Generation of antigen-presenting cells from tumor-infiltrated CD11b myeloid cells with DNA demethylating agent 5-aza-2′-deoxycytidine

Authors: Irina Daurkin, Evgeniy Eruslanov, Johannes Vieweg, Sergei Kusmartsev

Published in: Cancer Immunology, Immunotherapy | Issue 5/2010

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Abstract

Tumor-recruited CD11b myeloid cells, including myeloid-derived suppressor cells, play a significant role in tumor progression, as these cells are involved in tumor-induced immune suppression and tumor neovasculogenesis. On the other hand, the tumor-infiltrated CD11b myeloid cells could potentially be a source of immunostimulatory antigen-presenting cells (APCs), since most of these cells represent common precursors of both dendritic cells and macrophages. Here, we investigated the possibility of generating mature APCs from tumor-infiltrated CD11b myeloid cells. We demonstrate that in vitro exposure of freshly excised mouse tumors to DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine (decitabine, AZA) results in selective elimination of tumor cells, but, surprisingly it also enriches CD45+ tumor-infiltrated cells. The majority of “post-AZA” surviving CD45+ tumor-infiltrated cells were represented by CD11b myeloid cells. A culture of isolated tumor-infiltrated CD11b cells in the presence of AZA and GM-CSF promoted their differentiation into mature F4/80/CD11c/MHC class II-positive APCs. These tumor-derived myeloid APCs produced substantially reduced amounts of immunosuppressive (IL-13, IL-10, PGE2), pro-angiogenic (VEGF, MMP-9) and pro-inflammatory (IL-1beta, IL-6, MIP-2) mediators than their precursors, freshly isolated tumor-infiltrated CD11b cells. Vaccinating naïve mice with ex vivo generated tumor-derived APCs resulted in the protection of 70% mice from tumor outgrowth. Importantly, no loading of tumor-derived APC with exogenous antigen was needed to stimulate T cell response and induce the anti-tumor effect. Collectively, our results for the first time demonstrate that tumor-infiltrated CD11b myeloid cells can be enriched and differentiated in the presence of DNA demethylating agent 5-aza-2′-deoxycytidine into mature tumor-derived APCs, which could be used for cancer immunotherapy.
Literature
1.
2.
Balkwill F, Charles KA, Mantovani A (2005) Smoldering and polarized inflammation in the initiation and promotion of malignant disease. Cancer Cell 7(3):211–217CrossRefPubMed
3.
Murdoch C, Muthana M, Coffelt SB (2008) The role of myeloid cells in the promotion of tumour angiogenesis. Nat Rev Cancer 8(8):618–631CrossRefPubMed
4.
Yang L, DeBusk L, Fukuda K et al (2004) Expansion of myeloid immune suppressor Gr+ CD11b+ cells in tumor-bearing host directly promotes tumor angiogenesis. Cancer Cell 6(4):409–421CrossRefPubMed
5.
Grunewald M, Avraham I, Dor Y et al (2006) VEGF-induced adult neovascularization: recruitment, retention, and role of accessory cells. Cell 124(1):175–189CrossRefPubMed
6.
Ahn GO, Brown JM (2008) Matrix metalloproteinase-9 is required for tumor vasculogenesis but not for angiogenesis: role of bone marrow-derived myelomonocytic cells. Cancer Cell 13(3):193–205CrossRefPubMed
7.
Kaplan RN, Riba RD, Zacharoulis S et al (2005) VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438(7069):820–827CrossRefPubMed
8.
Hiratsuka S, Watanabe A, Aburatani H, Maru Y (2007) Tumour-mediated upregulation of chemoattractants and recruitment of myeloid cells predetermines lung metastases. Nat Cell Biol 8(12):1369–1375CrossRef
9.
Saio M, Radoja S, Marino M, Frey AB (2001) Tumor-infiltrating macrophages induce apoptosis in activated CD8(+) T cells by a mechanism requiring cell contact and mediated by both the cell-associated form of TNF and nitric oxide. J Immunol 167(10):5583–5593PubMed
10.
Rodriguez PC, Quiceno DG, Zabaleta J et al (2004) Arginase I production in the tumor microenvironment by mature myeloid cells inhibits T-cell receptor expression and antigen-specific T-cell responses. Cancer Res 64(16):5839–5849CrossRefPubMed
11.
Kusmartsev S, Gabrilovich D (2005) STAT1 signaling regulates tumor-associated macrophage-mediated T cell deletion. J Immunol 174(8):4880–4891PubMed
12.
Yu H, Kortylewski M, Pardoll D (2007) Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment. Nat Rev Immunol 7(1):41–51CrossRefPubMed
13.
Eruslanov E, Kaliberov S, Daurkin I et al (2009) Altered expression of 15-hydroxyprostaglandin dehydrogenase in tumor-infiltrated CD11b myeloid cells: a mechanism for immune evasion in cancer. J Immunol 182(12):7548–7557CrossRefPubMed
14.
Zhang B, Bowerman NB, Salama JK et al (2007) Induced sensitization of tumor stroma leads to eradication of established cancer by T cells. J Exp Med 204(1):49–55CrossRefPubMed
15.
Talmadge J, Donkor M, Scholar E (2007) Inflammatory cell infiltration of tumors: Jekyll or Hyde. Cancer Metastasis Rev 26(3–4):373–400CrossRefPubMed
16.
Kusmartsev S, Gabrilovich D (2006) Role of immature myeloid cells in mechanisms of immune evasion in cancer. Cancer Immunol Immunother 55(3):237–245CrossRefPubMed
17.
Sica A, Bronte V (2007) Altered macrophage differentiation and immune dysfunction in tumor development. J Clin Invest 117(5):1155–1166CrossRefPubMed
18.
Nefedova Y, Huang M, Kusmartsev S et al (2004) Hyperactivation of STAT3 is involved in abnormal differentiation of dendritic cells in cancer. J Immunol 172(1):464–474PubMed
19.
Gabrilovich D, Chen HL, Girgis KR et al (1996) Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat Med 2(10):1096–1103CrossRefPubMed
20.
Sombroek CC, Stam AGM, Masterson AJ et al (2002) Prostanoids play a major role in the primary tumor-induced inhibition of dendritic cell differentiation. J Immunol 168(9):4333–4343PubMed
21.
Sharma S, Stolina M, Yang SC et al (2003) Tumor cyclooxygenase 2-dependent suppression of dendritic cell function. Clin Cancer Res 9:961–968PubMed
22.
Talmadge J, Hood K, Zobel L, Shafer L, Coles M, Toth B (2007) Chemoprevention by cyclooxygenase-2 inhibition reduces immature myeloid suppressor cell expansion. Int Immunopharmacol 7(2):140–151CrossRefPubMed
23.
Sinha P, Clements VK, Fulton AM, Ostrand-Rosenberg S (2007) Prostaglandin E2 promotes tumor progression by inducing myeloid-derived suppressor cells. Cancer Res 67(9):4507–4513CrossRefPubMed
24.
Cheng P, Corzo C, Luetteke N et al (2008) Inhibition of dendritic cell differentiation and accumulation of myeloid-derived suppressor cells in cancer is regulated by S100A9 protein. J Exp Med 205(10):2235–2249CrossRefPubMed
25.
Stresemann C, Lyko F (2008) Modes of action of the DNA methyltransferase inhibitors azacytidine and decitabine. Int J Cancer 123(1):8–13CrossRefPubMed
26.
Mantovani A, Schioppa T, Porta C, Allavena P, Antonio Sica A (2006) Role of tumor-associated macrophages in tumor progression and invasion. Cancer Metastasis Rev 25(3):315–322CrossRefPubMed
27.
Biswas SK, Gangi L, Paul S et al (2005) A distinct and unique transcriptional program expressed by tumor-associated macrophages (defective NF-kappaB and enhanced IRF-3/STAT1 activation). Blood 107(5):2112–2122CrossRefPubMed
28.
29.
Tai HH, Cho H, Tong M, Ding Y (2006) NAD+-linked 15-hydroxyprostaglandin dehydrogenase: structure and biological functions. Curr Pharm Des 12(8):955–962CrossRefPubMed
30.
Kusmartsev S, Gabrilovich D (2002) Immature myeloid cells and cancer-associated immune suppression. Cancer Immunol Immunother 51(2):293–298CrossRefPubMed
31.
Sinha P, Clements VK, Miller S, Ostrand-Rosenberg S (2005) Tumor immunity: a balancing act between T cell activation, macrophage activation and tumor-induced immune suppression. Cancer Immunol Immunother 54(11):1137–1142CrossRefPubMed
32.
Fu YX, Watson GA, Kasahara M, Lopez DM (1991) The role of tumor-derived cytokines on the immune system of mice bearing a mammary adenocarcinoma. I. Induction of regulatory macrophages in normal mice by the in vivo administration of rGM-CSF. J Immunol 146(2):783–789PubMed
33.
Young MRI, Wright MA, Matthews JP, Malik I, Prechel M (1996) Suppression of T cell proliferation by tumor-induced granulocyte-macrophage progenitor cells producing transforming growth factor-β and nitric oxide. J Immunol 156(5):1916–1921PubMed
34.
Bronte V, Chappell DB, Apolloni E et al (1999) Unopposed production of granulocyte-macrophage colony-stimulating factor by tumors inhibits CD8+ T cell responses by dysregulating antigen-presenting cell maturation. J Immunol 162(10):5728–5737PubMed
35.
Kusmartsev S, Li Y, Chen SH (2000) Gr-1+ myeloid cells derived from tumor-bearing mice inhibit primary T cell activation induced through CD3/CD28 co-stimulation. J Immunol 165(2):779–785PubMed
36.
Gabrilovich D, Velders MP, Sotomayor EM, Kast WM (2001) Mechanism of immune dysfunction in cancer mediated by immature Gr-1+ myeloid cells. J Immunol 166(9):5398–5406PubMed
37.
Melani C, Chiodoni C, Forni G, Colombo MP (2003) Myeloid cell expansion elicited by the progression of spontaneous mammary carcinomas in c-erbB-2 transgenic BALB/c mice suppresses immune reactivity. Blood 102(6):2138–2145CrossRefPubMed
38.
Liu Y, Van Ginderachter J, Brys L, De Baetselier P, Raes G, Geldhof A (2003) Nitric oxide-independent CTL suppression during tumor progression: association with arginase-producing (M2) myeloid cells. J Immunol 170(10):5064–5074PubMed
39.
Rodriguez PC, Hernandez CP, David Quiceno D et al (2005) Arginase I in myeloid suppressor cells is induced by COX-2 in lung carcinoma. J Exp Med 202(7):931–939CrossRefPubMed
40.
Setiadi AF, Omilusik K, David MD et al (2008) Epigenetic enhancement of antigen processing and presentation promotes immune recognition of tumors. Cancer Res 68(7):9601–9607CrossRefPubMed
41.
Villagra A, Cheng F, Wang HW et al (2008) The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance. Nat Immunol 10(1):92–100CrossRefPubMed
42.
Chang YC, Chen TC, Lee CT et al (2008) Epigenetic control of MHC class II expression in tumor-associated macrophages by decoy receptor 3. Blood 111(10):5054–5063CrossRefPubMed
43.
Guo ZS, Hong JA, Irvine KR et al (2006) De novo induction of a cancer/testis antigen by 5-aza-2′-deoxycytidine augments adoptive immunotherapy in a murine tumor model. Cancer Res 66(2):1105–1113CrossRefPubMed
44.
Fonsatti E, Nicolay HJ, Sigalotti L et al (2007) Functional up-regulation of human leukocyte antigen class I antigens expression by 5-aza-2′-deoxycytidine in cutaneous melanoma: immunotherapeutic implications. Clin Cancer Res 13(11):3333–3338CrossRefPubMed
45.
Kozar K, Kamiński R, Switaj T et al (2003) Interleukin 12-based immunotherapy improves the antitumor effectiveness of a low-dose 5-Aza-2′-deoxycitidine treatment in L1210 leukemia and B16F10 melanoma models in mice. Clin Cancer Res 9(8):3124–3133PubMed
46.
Preynat-Seauve O, Schuler P, Contassot E, Beermann F, Huard B, French LE (2006) Tumor-infiltrating dendritic cells are potent antigen-presenting cells able to activate T cells and mediate tumor rejection. J Immunol 176(1):61–67PubMed
Metadata
Title
Generation of antigen-presenting cells from tumor-infiltrated CD11b myeloid cells with DNA demethylating agent 5-aza-2′-deoxycytidine
Authors
Irina Daurkin
Evgeniy Eruslanov
Johannes Vieweg
Sergei Kusmartsev
Publication date
01-05-2010
Publisher
Springer-Verlag
Published in
Cancer Immunology, Immunotherapy / Issue 5/2010
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI
https://doi.org/10.1007/s00262-009-0786-4

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