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

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Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

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.

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Acknowledgments

We gratefully thank Lisa Williams for assistance with manuscript preparation.

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Authors and Affiliations

  1. Department of Urology, Shands Cancer Center, College of Medicine, University of Florida, Gainesville, FL, 32610, USA

    Irina Daurkin, Evgeniy Eruslanov, Johannes Vieweg & Sergei Kusmartsev

  2. Cancer and Genetics Research Center, University of Florida, 1376 Mowry Rd, Rm. 459, P.O. Box 103633, Gainesville, FL, 32610, USA

    Sergei Kusmartsev

Authors
  1. Irina Daurkin
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  2. Evgeniy Eruslanov
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  4. Sergei Kusmartsev
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Correspondence to Sergei Kusmartsev.

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Daurkin, I., Eruslanov, E., Vieweg, J. et al. Generation of antigen-presenting cells from tumor-infiltrated CD11b myeloid cells with DNA demethylating agent 5-aza-2′-deoxycytidine. Cancer Immunol Immunother 59, 697–706 (2010). https://doi.org/10.1007/s00262-009-0786-4

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  • DOI: https://doi.org/10.1007/s00262-009-0786-4

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