title: NK Cell-Mediated Antitumor Effects of a Folate-Conjugated Immunoglobulin Are Enhanced by Cytokines.
abstract: Optimally effective antitumor therapies would not only activate immune effector cells but also engage them at the tumor. Folate conjugated to immunoglobulin (F-IgG) could direct innate immune cells with Fc receptors to folate receptor-expressing cancer cells. F-IgG bound to human KB and HeLa cells, as well as murine L1210JF, a folate receptor (FR)-overexpressing cancer cell line, as determined by flow cytometry. Recognition of F-IgG by natural killer (NK) cell Fc receptors led to phosphorylation of the ERK transcription factor and increased NK cell expression of CD69. Lysis of KB tumor cells by NK cells increased by about 5-fold after treatment with F-IgG, an effect synergistically enhanced by treatment with IL2, IL12, IL15, or IL21 (P< 0.001). F-IgG also enhanced the lysis of chronic lymphocytic leukemia cells by autologous NK cells. NK cells significantly increased production of IFNγ, MIP-1α, and RANTES in response to F-IgG-coated KB target cells in the presence of the NK cell-activating cytokine IL12, and these coculture supernatants induced significant T-cell chemotaxis (P< 0.001). F-IgG-coated targets also stimulated FcR-mediated monocyte effector functions. Studies in a murine leukemia model confirmed the intratumoral localization and antitumor activity of F-IgG, as well as enhancement of its effects by IL12 (P =0.05). The antitumor effect of this combination was dependent on NK cells and led to decreased tumor cell proliferation in vivo Thus, F-IgG can induce an immune response against FR-positive tumor cells that is mediated by NK cells and can be augmented by cytokine therapy.
authors: Department of Neurosurgery, The Ohio State University, Columbus, OH.
authors: Alena C
authors: AC
authors: Jaime-Ramirez
authors: Department of Biomedical Sciences Graduate Program, College of Medicine, The Ohio State University, Columbus, OH.
authors: Elizabeth
authors: E
authors: McMichael
authors: Karmanos Cancer Institute, Detroit, MI.
authors: SriVidya
authors: S
authors: Kondadasula
authors: Department of Surgery, The Ohio State University, Columbus, OH.
authors: Cassandra C
authors: CC
authors: Skinner
authors: Arthur G. James Comprehensive Cancer Center and Solove Research Institute, The Ohio State University, Columbus, OH.
authors: Bethany L
authors: BL
authors: Mundy-Bosse
authors: Department of Surgery, The Ohio State University, Columbus, OH.
authors: Eric
authors: E
authors: Luedke
authors: Riverside Breast Specialists, Westerville, OH.
authors: Natalie B
authors: NB
authors: Jones
authors: Breast Cancer Center, Memorial Cancer Institute, Pembroke Pines, FL.
authors: Aruna
authors: A
authors: Mani
authors: OncoMed Pharmaceuticals Inc., Redwood City, CA.
authors: Julie
authors: J
authors: Roda
authors: Wright State University School of Medicine, Dayton, OH.
authors: Volodymyr
authors: V
authors: Karpa
authors: College of Pharmacy, The Ohio State University, Columbus, OH.
authors: Hong
authors: H
authors: Li
authors: College of Pharmacy, The Ohio State University, Columbus, OH.
authors: Jilong
authors: J
authors: Li
authors: Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Internal Medicine, The Ohio State University, Columbus, OH.
authors: Saranya
authors: S
authors: Elavazhagan
authors: Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH.
authors: Krista M
authors: KM
authors: La Perle
authors: Grady Memorial Hospital, Atlanta, GA.
authors: Alessandra C
authors: AC
authors: Schmitt
authors: Merck & Co, Kenilworth, NJ.
authors: Yanhui
authors: Y
authors: Lu
authors: Center for Biostatistics, The Ohio State University, Columbus, OH.
authors: Xiaoli
authors: X
authors: Zhang
authors: Center for Biostatistics, The Ohio State University, Columbus, OH.
authors: Xueliang
authors: X
authors: Pan
authors: Arthur G. James Comprehensive Cancer Center and Solove Research Institute, The Ohio State University, Columbus, OH.
authors: Hsaioyin
authors: H
authors: Mao
authors: Division of Hematology, The Ohio State University, Columbus, OH.
authors: Melanie
authors: M
authors: Davis
authors: Center for Biostatistics, The Ohio State University, Columbus, OH.
authors: David
authors: D
authors: Jarjoura
authors: Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Internal Medicine, The Ohio State University, Columbus, OH.
authors: Jonathan P
authors: JP
authors: Butchar
authors: College of Pharmacy, The Ohio State University, Columbus, OH.
authors: Ming
authors: M
authors: Poi
authors: College of Pharmacy, The Ohio State University, Columbus, OH.
authors: Mitch
authors: M
authors: Phelps
authors: Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Internal Medicine, The Ohio State University, Columbus, OH.
authors: Susheela
authors: S
authors: Tridandapani
authors: Division of Hematology, The Ohio State University, Columbus, OH.
authors: John C
authors: JC
authors: Byrd
authors: Arthur G. James Comprehensive Cancer Center and Solove Research Institute, The Ohio State University, Columbus, OH.
authors: Michael A
authors: MA
authors: Caligiuri
authors: College of Pharmacy, The Ohio State University, Columbus, OH.
authors: Robert J
authors: RJ
authors: Lee
authors: Department of Biomedical Sciences Graduate Program, College of Medicine, The Ohio State University, Columbus, OH.|Department of Surgery, The Ohio State University, Columbus, OH.|Arthur G. James Comprehensive Cancer Center and Solove Research Institute, The Ohio State University, Columbus, OH.
authors: William E
authors: WE
authors: Carson
mesh_terms: D000818:Animals; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism*; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D058975:Folate Receptor 1 / Q000235:genetics / Q000378:metabolism; D005492:Folic Acid / Q000008:administration & dosage*; D015870:Gene Expression; D006801:Humans; D018796:Immunoconjugates / Q000276:immunology*; D007074:Immunoglobulin G / Q000276:immunology; D056747:Immunomodulation; D018664:Interleukin-12 / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D047368:Tumor Burden / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
chemical_list: D016207:Cytokines; D058975:Folate Receptor 1; D018796:Immunoconjugates; D007074:Immunoglobulin G; D018664:Interleukin-12; D005492:Folic Acid