A novel dendritic cell subset supporting the concept of tumor immunoediting: IFN producing Killer Dendritic cell (IKDC)

Proc Amer Assoc Cancer Res, Volume 47, 2006 4874 IFNγ is a key immunomodulator pivotal in the host defense against tumor progression. Pionnering studies have demonstrated that IFNγ mediated-signaling pathways are critical against tumor development in recombination activation gene deficient mice. Here we show that the main source of IFNγ is not the conventional NK cell but a subset of B220+Ly6C- dendritic cells that are atypical in thus far that they express NK cell surface molecules (Dx5, NK1.1, NKG2D, Ly49). They represent 1% of splenic CD11c+ cells in naive animals, can be expanded by 5 fold by immunotherapy combining c-kit tyrosine kinase inhibitors and IL-2 or Flt3L and traffick into tumor beds where they constitute up to 20% of tumor infiltrating CD11c+. Upon contact with a variety of tumor cells that are poorly recognized by NK cells, B220+NK1.1+ dendritic cells secrete high levels of IFNγ and mediate TRAIL-dependent tumor cell lysis. During therapy with imatinib mesylate and IL-2, tumor regression depends on TRAIL molecules, NK1.1 expressing cells and IFN type II receptors, suggesting a role for B220+NK1.1+ dendritic cells in tumor shrinkage. Adoptive transfer of these Interferon-producing Killer Dendritic Cells (IKDC) into tumor-bearing Rag-/-IL-2Rγ-/- mice prevented tumor outgrowth whereas conventional NK cells failed to do so. IKDC can be found in Rag-/-IL-2Rγ-/- mice, they diverge from the NK cell lineage. Moreover, they exhibit a typical morphology distinguishable from classical myeloid DC or plasmacytoid DC or NK cells and are capable of antigen presentation following TLR4 and 9 triggering. We identified IKDC as pivotal sensors and effectors of the innate anti-tumor immune response (Taieb J et al Nature Medicine, in revision in back to back with D.Pardoll’s manuscript).