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We recently reported a novel subset of multitasking immune cells: the interferon-producing killer dendritic cell (IKDC), initially described as CD11c+B220+Gr1/Ly6C- tumor infiltrating cells in regressing B16F10 melanoma following a combination therapy with Gleevec®/IL-2 (Taieb J. et al. Nat. Med. 2006). IKDC exhibit unique phenotypic and functional features that they share with both dendritic cells (DC) and NK cells. They are found in all lymphoid organs and represent up to 1% of splenic CD11c+ cells expressing not only MHC class II but also CD122, NK1.1 and Dx5 molecules. At steady state, IKDC do not express co-stimulatory molecules but stain with anti-L selectin, chemerin R23 and CCR7 antibodies, suggesting that they could traffic from blood to lymph nodes. Like NK cells, IKDC depend on IL-15/IL-15Rα for their ontogeny and differentiation. However, in contrast to bona fide NK cells, IKDC are able to kill a variety of tumor cell lines with a unique recognition pattern and over-express GATA2 and PU1 while CD11c-B220-NK1.1+ cells rather express GATA3 and IL-7Rα. At steady state, they do not exhibit high levels of TLR expression or APC function. Here we report that their optimal ex vivo proliferation relies upon stromal IL-15Rα expressing MS5 and rIL-15 which allowed up to 20 fold expansion of IKDC in one week. IL-15 is not only indispensable for their homeostasis but also for their activation status. IL-15 promotes the upregulation of TLR3 and TLR4 transcription levels, allowing the synergistic response with LPS for MCP-1, MIP-1α, IP-10 and RANTES secretion. Moreover, IL-15 synergizes with type 1 IFN for IKDC expression of CCR2 and its ligand MCP-1. Finally, IL-15 markedly upregulates expression of the killing machinery (perforine, granzyme, TRAIL) endowing IKDC with potent lytic function. We demonstrated that the combination of Gleevec® and IL-2 could induce IKDC recruitment into tumor beds (by 5 fold) and expansion of IKDC in an IL-15 dependent manner. Moreover, the antitumor efficacy of Gleevec® and IL-2 was markedly dependent on type 1 IFNR and TRAIL. Finally, direct inoculation of IL-15 expanded IKDC into tumors hampered tumor progression. These data indicate that IKDC represent a novel subset of antitumor immune effectors and early mediators of IL-15 -dependent inflammatory processes.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA