Article ; Online: Generation of antigen-presenting cells from tumor-infiltrated CD11b myeloid cells with DNA demethylating agent 5-aza-2'-deoxycytidine.
Cancer immunology, immunotherapy : CII
2009 Volume 59, Issue 5, Page(s) 697–706
Abstract: ... methyltransferase inhibitor 5-aza-2'-deoxycytidine (decitabine, AZA) results in selective elimination of tumor cells ... infiltrated CD11b myeloid cells can be enriched and differentiated in the presence of DNA demethylating agent ... infiltrated CD11b myeloid cells. We demonstrate that in vitro exposure of freshly excised mouse tumors to DNA ...
| 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, PGE(2)), 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. |
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| MeSH term(s) | Animals ; Antigen-Presenting Cells/cytology ; Antigen-Presenting Cells/drug effects ; Antigen-Presenting Cells/transplantation ; Antimetabolites, Antineoplastic/pharmacology ; Azacitidine/analogs & derivatives ; Azacitidine/pharmacology ; Blotting, Western ; CD11b Antigen/metabolism ; Cancer Vaccines/immunology ; Cancer Vaccines/therapeutic use ; Cell Differentiation/drug effects ; Cell Differentiation/immunology ; Cell Separation ; Cytokines/biosynthesis ; Decitabine ; Female ; Flow Cytometry ; Immunotherapy/methods ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Myeloid Cells/cytology ; Myeloid Cells/drug effects ; Myeloid Cells/transplantation ; Neoplasms, Experimental/therapy ; Reverse Transcriptase Polymerase Chain Reaction |
| Chemical Substances | Antimetabolites, Antineoplastic ; CD11b Antigen ; Cancer Vaccines ; Cytokines ; Decitabine (776B62CQ27) ; Azacitidine (M801H13NRU) |
| Language | English |
| Publishing date | 2009-10-31 |
| Publishing country | Germany |
| Document type | Journal Article |
| ZDB-ID | 195342-4 |
| ISSN | 1432-0851 ; 0340-7004 |
| ISSN (online) | 1432-0851 |
| ISSN | 0340-7004 |
| DOI | 10.1007/s00262-009-0786-4 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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