title: Helper role of NK cells during the induction of anticancer responses by dendritic cells.
abstract: Recent reports demonstrate that natural killer (NK) cells and dendritic cells (DC) support each other's activity in a positive feedback. We observed that activated NK cells induce the maturation of DCs into stable type-1 polarized DCs (DC1), characterized by up to 100-fold enhanced ability to produce IL-12p70 in response to subsequent interaction with Th cells. DC1 induction depends on NK cell-produced IFN-gamma and TNF-alpha, with a possible involvement of additional factors. DC1, induced by NK cells or by NK cell-related soluble factors, are stable, resistant to tumor-related suppressive factors, and show strongly enhanced ability to induce Th1 and CTL responses. In analogy to resting T cells, the induction of "helper" function of NK cells relies on a two-signal activation paradigm. While NKG2D-dependent tumor cell recognition is sufficient to induce the cytotoxic "effector" function of NK cells, the induction of "NK cell help" requires additional signals from type-1 IFNs, products of virally-infected cells, or from IL-2. Compared to non-polarized DCs currently-used in clinical trials, DC1s act as superior inducers of anti-cancer CTL responses during in vitro sensitization. The current data provides rationale for the clinical use of DC1s in cancer and chronic infections (such as HIV), as a new generation DC-based vaccines, uniquely combining fully mature DC status with an elevated, rather than "exhausted" ability to produce bioactive IL-12p70. We are currently implementing stage I/II clinical trials, testing the effectiveness of DC1s induced by NK cells or by NK cell-related factors, as therapeutic vaccines against melanoma.
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213-1863, USA. kalinskip@upmc.edu
authors.forename: Pawel
authors.initials: P
authors.lastname: Kalinski
authors.forename: Adam
authors.initials: A
authors.lastname: Giermasz
authors.forename: Yutaro
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Per
authors.initials: P
authors.lastname: Basse
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Storkus
authors.forename: John M
authors.initials: JM
authors.lastname: Kirkwood
authors.forename: Robbie B
authors.initials: RB
authors.lastname: Mailliard
mesh_terms: D002450:Cell Communication / Q000276:immunology*; D002986:Clinical Trials as Topic; D003713:Dendritic Cells / Q000276:immunology*; D006801:Humans; D007167:Immunotherapy; D007694:Killer Cells, Natural / Q000276:immunology*; D009369:Neoplasms / Q000276:immunology* / Q000628:therapy