Cancer Immunology, Immunotherapy

, Volume 59, Issue 5, pp 697–706 | Cite as

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

  • Irina Daurkin
  • Evgeniy Eruslanov
  • Johannes Vieweg
  • Sergei Kusmartsev
Original Article

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.

Keywords

Tumor-infiltrated myeloid cells 5-Aza-2′-deoxycytidine Dendritic cells 

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Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Irina Daurkin
    • 1
  • Evgeniy Eruslanov
    • 1
  • Johannes Vieweg
    • 1
  • Sergei Kusmartsev
    • 1
    • 2
  1. 1.Department of Urology, Shands Cancer Center, College of MedicineUniversity of FloridaGainesvilleUSA
  2. 2.Cancer and Genetics Research CenterUniversity of FloridaGainesvilleUSA

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