title: Immune rejection of a large sarcoma following cyclophosphamide and IL-12 treatment requires both NK and NK T cells and is associated with the induction of a novel NK T cell population.
abstract: Combined immunotherapy with cyclophosphamide (Cy) and IL-12, but not IL-12 alone, stimulates eradication of a large established solid tumor (20 mm), MCA207, a methylcholanthrene-induced murine sarcoma. In these studies we demonstrate that NK1.1(+) cells and CD1d-dependent NK T cells each play important yet distinct roles in regression of a large tumor in response to Cy and IL-12, and we define a novel NK T cell subset, selectively increased by this treatment. Mice depleted of NK1.1(+) cells demonstrated more rapid initial tumor growth and prolonged tumor regression following treatment, but tumors were eventually eradicated. In contrast, initial tumor regression following therapy was unimpaired in CD1d(-/-) mice, which are deficient in most NK T cells, but tumors recurred. No tumor regression occurred following Cy and IL-12 therapy in CD1d(-/-) mice that were depleted of NK1.1(+) cells. We found that Cy and IL-12 induced the selective increase in liver and spleen lymphocytes of a unique NK T subpopulation (DX5(+)NK1.1(-)CD3(+)). These cells were not induced by treatment in CD1d(-/-) mice. Our studies demonstrate a contribution of both NK and NK T cells to the Cy- and IL-12-stimulated anti-tumor response. We describe the selective induction of a distinct NK T cell subset by Cy and IL-12 therapy, not seen following IL-12 therapy alone, which we suggest may contribute to the successful anti-tumor response induced by this immunotherapeutic regimen.
authors.affiliation: Department of Medicine, University of California, San Francisco, CA 94143, USA.
authors.forename: C
authors.initials: C
authors.lastname: Karnbach
authors.forename: M R
authors.initials: MR
authors.lastname: Daws
authors.forename: E C
authors.initials: EC
authors.lastname: Niemi
authors.forename: M C
authors.initials: MC
authors.lastname: Nakamura
mesh_terms: D000818:Animals; D000941:Antigens / Q000378:metabolism; D018949:Antigens, CD1 / Q000235:genetics / Q000378:metabolism; D055610:Antigens, CD1d; D000950:Antigens, Ly; D000954:Antigens, Surface; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage*; D017252:CD3 Complex / Q000378:metabolism; D003520:Cyclophosphamide / Q000008:administration & dosage*; D005260:Female; D018664:Interleukin-12 / Q000008:administration & dosage*; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology*; D037181:Lectins, C-Type; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055651:NK Cell Lectin-Like Receptor Subfamily B; D011506:Proteins / Q000378:metabolism; D012513:Sarcoma, Experimental / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology*
chemical_list: D000941:Antigens; D018949:Antigens, CD1; D055610:Antigens, CD1d; D000950:Antigens, Ly; D000954:Antigens, Surface; D018906:Antineoplastic Agents, Alkylating; D017252:CD3 Complex; C527211:Klrb1c protein, mouse; D037181:Lectins, C-Type; D055651:NK Cell Lectin-Like Receptor Subfamily B; D011506:Proteins; D018664:Interleukin-12; D003520:Cyclophosphamide