title: IL-21 Enhances Natural Killer Cell Response to Cetuximab-Coated Pancreatic Tumor Cells.
abstract: OBJECTIVE
  Alternative strategies to EGFR blockage by mAbs is necessary to improve the efficacy of therapy in patients with locally advanced or metastatic pancreatic cancer. One such strategy includes the use of NK cells to clear cetuximab-coated tumor cells, as need for novel therapeutic approaches to enhance the efficacy of cetuximab is evident. We show that IL-21 enhances NK cell-mediated effector functions against cetuximab-coated pancreatic tumor cells irrespective of KRAS mutation status.
  
  
  METHODS
  NK cells from normal donors or donors with pancreatic cancer were used to assess ADCC, IFN-γ release, and T-cell chemotaxis toward human pancreatic cancer cell lines. The in vivo efficacy of IL-21 in combination with cetuximab was evaluated in a subcutaneous and intraperitoneal model of pancreatic cancer.
  
  
  RESULTS
  NK cell lysis of cetuximab-coated wild-type and mutant kras pancreatic cancer cell lines were significantly higher following NK cell IL-21 treatment. In response to cetuximab-coated pancreatic tumor cells, IL-21-treated NK cells secreted significantly higher levels of IFN-γ and chemokines, increased chemotaxis of T cells, and enhanced NK cell signal transduction via activation of ERK and STAT1. Treatment of mice bearing subcutaneous or intraperitoneal EGFR-positive pancreatic tumor xenografts with mIL-21 and cetuximab led to significant inhibition of tumor growth, a result further enhanced by the addition of gemcitabine.
  
  
  CONCLUSIONS
  These results suggest that cetuximab treatment in combination with IL-21 adjuvant therapy in patients with EGFR-positive pancreatic cancer results in significant NK cell activation, irrespective of KRAS mutation status, and may be a potential therapeutic strategy. Clin Cancer Res; 23(2); 489-502. ©2016 AACR.
authors.affiliation: Biomedical Sciences Graduate Program, College of Medicine, The Ohio State University, Columbus, Ohio.
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: McMichael
authors.affiliation: Department of Neurosurgery, The Ohio State University, Columbus, Ohio.
authors.forename: Alena Cristina
authors.initials: AC
authors.lastname: Jaime-Ramirez
authors.affiliation: Division of Surgical Oncology, Department of Surgery, The Ohio State University, Columbus, Ohio.
authors.forename: Kristan D
authors.initials: KD
authors.lastname: Guenterberg
authors.affiliation: Division of Surgical Oncology, Department of Surgery, The Ohio State University, Columbus, Ohio.
authors.forename: Eric
authors.initials: E
authors.lastname: Luedke
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Lakhvir S
authors.initials: LS
authors.lastname: Atwal
authors.affiliation: Biomedical Sciences Graduate Program, College of Medicine, The Ohio State University, Columbus, Ohio.
authors.forename: Amanda R
authors.initials: AR
authors.lastname: Campbell
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Armika S
authors.initials: AS
authors.lastname: Tatum
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Sri Vidya
authors.initials: SV
authors.lastname: Kondadasula
authors.affiliation: Center for Biostatistics, The Ohio State University, Columbus, Ohio.
authors.forename: Xiaokui
authors.initials: X
authors.lastname: Mo
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine, The Ohio State University, Columbus, Ohio.
authors.forename: Susheela
authors.initials: S
authors.lastname: Tridandapani
authors.affiliation: Division of Surgical Oncology, Department of Surgery, The Ohio State University, Columbus, Ohio.
authors.forename: Mark
authors.initials: M
authors.lastname: Bloomston
authors.affiliation: Division of Surgical Oncology, Department of Surgery, The Ohio State University, Columbus, Ohio.
authors.forename: E Christopher
authors.initials: EC
authors.lastname: Ellison
authors.affiliation: Department of Radiation Oncology, The Ohio State University, Columbus, Ohio.
authors.forename: Terence M
authors.initials: TM
authors.lastname: Williams
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio.
authors.forename: Tanios
authors.initials: T
authors.lastname: Bekaii-Saab
authors.affiliation: Division of Surgical Oncology, Department of Surgery, The Ohio State University, Columbus, Ohio. william.carson@osumc.edu.|Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, Ohio.
authors.forename: William E
authors.initials: WE
authors.lastname: Carson
mesh_terms: D000818:Animals; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects; D045744:Cell Line, Tumor; D000068818:Cetuximab / Q000008:administration & dosage; D002633:Chemotaxis / Q000187:drug effects / Q000276:immunology; D005434:Flow Cytometry; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D007378:Interleukins / Q000276:immunology* / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays; D000098546:Interleukin-21
chemical_list: D007378:Interleukins; C117307:KRAS protein, human; D007371:Interferon-gamma; D016283:Proto-Oncogene Proteins p21(ras); D000098546:Interleukin-21; D000068818:Cetuximab