title: Soypeptide lunasin in cytokine immunotherapy for lymphoma.
abstract: Immunostimulatory cytokines can enhance anti-tumor immunity and are part of the therapeutic armamentarium for cancer treatment. We have previously reported that post-transplant lymphoma patients have an acquired deficiency of signal transducer and activator of transcription 4, which results in defective IFNγ production during clinical immunotherapy. With the goal of further improving cytokine-based immunotherapy, we examined the effects of a soybean peptide called lunasin that synergistically works with cytokines on natural killer (NK) cells. Peripheral blood mononuclear cells of healthy donors and post-transplant lymphoma patients were stimulated with or without lunasin in the presence of IL-12 or IL-2. NK activation was evaluated, and its tumoricidal activity was assessed using in vitro and in vivo tumor models. Chromatin immunoprecipitation assay was performed to evaluate the histone modification of gene loci that are regulated by lunasin and cytokine. Adding lunasin to IL-12- or IL-2-stimulated NK cells demonstrated synergistic effects in the induction of IFNG and GZMB involved in cytotoxicity. The combination of lunasin and cytokines (IL-12 plus IL-2) was capable of restoring IFNγ production by NK cells from post-transplant lymphoma patients. In addition, NK cells stimulated with lunasin plus cytokines displayed higher tumoricidal activity than those stimulated with cytokines alone using in vitro and in vivo tumor models. The underlying mechanism responsible for the effects of lunasin on NK cells is likely due to epigenetic modulation on target gene loci. Lunasin represents a different class of immune modulating agent that may augment the therapeutic responses mediated by cytokine-based immunotherapy.
authors.affiliation: Department of Biology, School of Science, Indiana University-Purdue University Indianapolis, 723 West Michigan Street, SL310, Indianapolis, IN, 46202, USA, huchang@iupui.edu.
authors.forename: Hua-Chen
authors.initials: HC
authors.lastname: Chang
authors.forename: David
authors.initials: D
authors.lastname: Lewis
authors.forename: Chun-Yu
authors.initials: CY
authors.lastname: Tung
authors.forename: Ling
authors.initials: L
authors.lastname: Han
authors.forename: Sarah M P
authors.initials: SM
authors.lastname: Henriquez
authors.forename: Larry
authors.initials: L
authors.lastname: Voiles
authors.forename: Ivan P
authors.initials: IP
authors.lastname: Lupov
authors.forename: David
authors.initials: D
authors.lastname: Pelloso
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Sinn
authors.forename: Karen E
authors.initials: KE
authors.lastname: Pollok
authors.forename: Ben O
authors.initials: BO
authors.lastname: de Lumen
authors.forename: Fang
authors.initials: F
authors.lastname: Li
authors.forename: Janice S
authors.initials: JS
authors.lastname: Blum
authors.forename: Shivani
authors.initials: S
authors.lastname: Srivastava
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Robertson
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic / Q000187:drug effects / Q000235:genetics; D019175:DNA Methylation / Q000187:drug effects; D004357:Drug Synergism; D053804:Granzymes / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D018664:Interleukin-12 / Q000008:administration & dosage / Q000276:immunology; D007376:Interleukin-2 / Q000008:administration & dosage / Q000276:immunology; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics; D008223:Lymphoma / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000008:administration & dosage*; D050797:STAT4 Transcription Factor / Q000235:genetics; D030262:Soybean Proteins / Q000008:administration & dosage*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000276:Adjuvants, Immunologic; C120514:GM2S-1 protein, soybean; D007376:Interleukin-2; D010446:Peptide Fragments; D050797:STAT4 Transcription Factor; D030262:Soybean Proteins; D018664:Interleukin-12; D007371:Interferon-gamma; C509213:GZMB protein, human; D053804:Granzymes