title: TLR2 agonist PSK activates human NK cells and enhances the antitumor effect of HER2-targeted monoclonal antibody therapy.
abstract: OBJECTIVE
  The therapeutic effect of trastuzumab monoclonal antibody (mAb) therapy has been shown to be partially dependent on functional natural killer (NK) cells. Novel agents that enhance NK cell function could potentially improve the antitumor effect of trastuzumab. We recently identified polysaccharide krestin (PSK), a natural product extracted from medicinal mushroom Trametes versicolor, as a potent toll-like receptor 2 (TLR2) agonist. This study was undertaken to evaluate the effect of PSK on human NK cells and the potential of using PSK to enhance HER2-targeted mAb therapy.
  
  
  METHODS
  Human peripheral blood mononuclear cells were stimulated with PSK to evaluate the effect of PSK on NK cell activation, IFN-γ production, cytotoxicity, and trastuzumab-mediated antibody-dependent cell-mediated cytotoxicity (ADCC). Whether the effect of PSK on NK cells is direct or indirect was also investigated. Then, in vivo experiment in neu transgenic (neu-T) mice was carried out to determine the potential of using PSK to augment the antitumor effect of HER2-targeted mAb therapy.
  
  
  RESULTS
  PSK activated human NK cells to produce IFN-γ and to lyse K562 target cells. PSK also enhanced trastuzumab-mediated ADCC against SKBR3 and MDA-MB-231 breast cancer cells. Both direct and interleukin-12-dependent indirect effects seem to be involved in the effect of PSK on NK cells. Oral administration of PSK significantly potentiated the antitumor effect of anti-HER2/neu mAb therapy in neu-T mice.
  
  
  CONCLUSIONS
  These results showed that PSK activates human NK cells and potentiates trastuzumab-mediated ADCC. Concurrent treatment with PSK and trastuzumab may be a novel way to augment the antitumor effect of trastuzumab.
authors.affiliation: Tumor Vaccine Group, Center for Translational Medicine in Women's Health, University of Washington, Seattle, Washington 98109, USA. hlu@u.washington.edu
authors.forename: Hailing
authors.initials: H
authors.lastname: Lu
authors.forename: Yi
authors.initials: Y
authors.lastname: Yang
authors.forename: Ekram
authors.initials: E
authors.lastname: Gad
authors.forename: Carol
authors.initials: C
authors.lastname: Inatsuka
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Wenner
authors.forename: Mary L
authors.initials: ML
authors.lastname: Disis
authors.forename: Leanna J
authors.initials: LJ
authors.lastname: Standish
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology; D019002:CD56 Antigen / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis / Q000276:immunology / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D011509:Proteoglycans / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000819:agonists*; D000068878:Trastuzumab; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D019002:CD56 Antigen; D016207:Cytokines; D007371:Interferon-gamma; D007376:Interleukin-2; D011509:Proteoglycans; D018719:Erb-b2 Receptor Tyrosine Kinases; D051195:Toll-Like Receptor 2; D000068878:Trastuzumab; C522918:NCAM1 protein, human; C495342:TLR2 protein, human; C010770:polysaccharide-K