title: Sustained effector function of IL-12/15/18-preactivated NK cells against established tumors.
abstract: Natural killer cell (NK cell)-based immunotherapy of cancer is hampered by the transient effector function of NK cells. Recently, mouse IL-12/15/18-preactivated NK cells were shown to persist with sustained effector function in vivo. Our study investigated the antitumor activity of such NK cells. A single injection of syngeneic IL-12/15/18-preactivated NK cells, but neither naive nor IL-15- or IL-2-pretreated NK cells, combined with irradiation substantially reduced growth of established mouse tumors. Radiation therapy (RT) was essential for the antitumor activity of transferred NK cells. IL-12/15/18-preactivated NK cells expressed high levels of IL-2Rα (CD25), and their rapid in vivo proliferation depended on IL-2 produced by CD4+ T cells. IL-12/15/18-preactivated NK cells accumulated in the tumor tissue and persisted at high cell numbers with potent effector function that required the presence of CD4+ T cells. RT greatly increased numbers and function of transferred NK cells. Human IL-12/15/18-preactivated NK cells also displayed sustained effector function in vitro. Our study provides a better understanding for the rational design of immunotherapies of cancer that incorporate NK cells. Moreover, our results reveal an essential role of CD4+ T cell help for sustained antitumor activity by NK cells linking adaptive and innate immunity.
authors.affiliation: Junior Research Group Innate Immunity, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Jing
authors.initials: J
authors.lastname: Ni
authors.forename: Matthias
authors.initials: M
authors.lastname: Miller
authors.forename: Ana
authors.initials: A
authors.lastname: Stojanovic
authors.forename: Natalio
authors.initials: N
authors.lastname: Garbi
authors.forename: Adelheid
authors.initials: A
authors.lastname: Cerwenka
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003131:Combined Modality Therapy; D006801:Humans; D007113:Immunity, Innate; D016219:Immunotherapy, Adoptive; D007371:Interferon-gamma / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D018664:Interleukin-12 / Q000008:administration & dosage; D019409:Interleukin-15 / Q000008:administration & dosage; D020382:Interleukin-18 / Q000008:administration & dosage; D007376:Interleukin-2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D008223:Lymphoma / Q000276:immunology / Q000532:radiotherapy / Q000628:therapy; D008546:Melanoma, Experimental / Q000276:immunology / Q000532:radiotherapy / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000276:immunology / Q000532:radiotherapy / Q000628:therapy*; D013154:Spleen / Q000276:immunology; D013997:Time Factors
chemical_list: D019409:Interleukin-15; D020382:Interleukin-18; D007376:Interleukin-2; D018664:Interleukin-12; D007371:Interferon-gamma