title: NKG2D recognition and perforin effector function mediate effective cytokine immunotherapy of cancer.
abstract: Single and combination cytokines offer promise in some patients with advanced cancer. Many spontaneous and experimental cancers naturally express ligands for the lectin-like type-2 transmembrane stimulatory NKG2D immunoreceptor; however, the role this tumor recognition pathway plays in immunotherapy has not been explored to date. Here, we show that natural expression of NKG2D ligands on tumors provides an effective target for some cytokine-stimulated NK cells to recognize and suppress tumor metastases. In particular, interleukin (IL)-2 or IL-12 suppressed tumor metastases largely via NKG2D ligand recognition and perforin-mediated cytotoxicity. By contrast, IL-18 required tumor sensitivity to Fas ligand (FasL) and surprisingly did not depend on the NKG2D-NKG2D ligand pathway. A combination of IL-2 and IL-18 stimulated both perforin and FasL effector mechanisms with very potent effects. Cytokines that stimulated perforin-mediated cytotoxicity appeared relatively more effective against tumor metastases expressing NKG2D ligands. These findings indicate that a rational choice of cytokines can be made given the known sensitivity of tumor cells to perforin, FasL, and tumor necrosis factor-related apoptosis-inducing ligand and the NKG2D ligand status of tumor metastases.
authors.affiliation: Cancer Immunology Program, Peter MacCallum Cancer Centre, Locked Bag 1, A'Beckett St., 8006, Victoria, Australia. mark.smyth@petermac.org
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
authors.forename: Jeremy
authors.initials: J
authors.lastname: Swann
authors.forename: Janice M
authors.initials: JM
authors.lastname: Kelly
authors.forename: Erika
authors.initials: E
authors.lastname: Cretney
authors.forename: Wayne M
authors.initials: WM
authors.lastname: Yokoyama
authors.forename: Andreas
authors.initials: A
authors.lastname: Diefenbach
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Sayers
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Hayakawa
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology; D016207:Cytokines / Q000276:immunology / Q000378:metabolism / Q000627:therapeutic use*; D053222:Fas Ligand Protein; D005434:Flow Cytometry; D007167:Immunotherapy / Q000379:methods*; D018664:Interleukin-12 / Q000276:immunology / Q000378:metabolism; D020382:Interleukin-18 / Q000276:immunology / Q000378:metabolism; D007376:Interleukin-2 / Q000276:immunology / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008024:Ligands; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D055655:NK Cell Lectin-Like Receptor Subfamily K; D009362:Neoplasm Metastasis / Q000628:therapy*; D052899:Pore Forming Cytotoxic Proteins; D011971:Receptors, Immunologic / Q000378:metabolism*; D055607:Receptors, Natural Killer Cell; D011994:Recombinant Proteins / Q000276:immunology / Q000378:metabolism / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
chemical_list: D016207:Cytokines; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D020382:Interleukin-18; D007376:Interleukin-2; C527086:Klrk1 protein, mouse; D008024:Ligands; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D055655:NK Cell Lectin-Like Receptor Subfamily K; D052899:Pore Forming Cytotoxic Proteins; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; D011994:Recombinant Proteins; C483886:perforin, mouse; D018664:Interleukin-12