TLR2 Agonist PSK Activates Human NK Cells and Enhances the Antitumor Effect of HER2-targeted Monoclonal Antibody Therapy

Overview

Journal Clin Cancer Res

Specialty Oncology

Date 2011 Sep 16

PMID 21918170

Citations 37

Authors

Hailing Lu

Yi Yang

Ekram Gad

Carol Inatsuka

Cynthia A Wenner

Mary L Disis

Leanna J Standish

Affiliations

Soon will be listed here.

Abstract

Purpose: 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.

Experimental Design: 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.

Conclusion: 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.

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References

Arnould L, Gelly M, Penault-Llorca F, Benoit L, Bonnetain F, Migeon C . Trastuzumab-based treatment of HER2-positive breast cancer: an antibody-dependent cellular cytotoxicity mechanism?. Br J Cancer. 2006; 94(2):259-67. PMC: 2361112. DOI: 10.1038/sj.bjc.6602930. View

Marcenaro E, Ferranti B, Falco M, Moretta L, Moretta A . Human NK cells directly recognize Mycobacterium bovis via TLR2 and acquire the ability to kill monocyte-derived DC. Int Immunol. 2008; 20(9):1155-67. DOI: 10.1093/intimm/dxn073. View

Baselga J, Perez E, Pienkowski T, Bell R . Adjuvant trastuzumab: a milestone in the treatment of HER-2-positive early breast cancer. Oncologist. 2006; 11 Suppl 1:4-12. DOI: 10.1634/theoncologist.11-90001-4. View

Parihar R, Dierksheide J, Hu Y, Carson W . IL-12 enhances the natural killer cell cytokine response to Ab-coated tumor cells. J Clin Invest. 2002; 110(7):983-92. PMC: 151155. DOI: 10.1172/JCI15950. View

Oba K, Teramukai S, Kobayashi M, Matsui T, Kodera Y, Sakamoto J . Efficacy of adjuvant immunochemotherapy with polysaccharide K for patients with curative resections of gastric cancer. Cancer Immunol Immunother. 2006; 56(6):905-11. PMC: 11030720. DOI: 10.1007/s00262-006-0248-1. View

Varker K, Terrell C, Welt M, Suleiman S, Thornton L, Andersen B . Impaired natural killer cell lysis in breast cancer patients with high levels of psychological stress is associated with altered expression of killer immunoglobin-like receptors. J Surg Res. 2007; 139(1):36-44. PMC: 1932802. DOI: 10.1016/j.jss.2006.08.037. View

Lanier L . NK cell recognition. Annu Rev Immunol. 2005; 23:225-74. DOI: 10.1146/annurev.immunol.23.021704.115526. View

Hart O, Athie-Morales V, OConnor G, Gardiner C . TLR7/8-mediated activation of human NK cells results in accessory cell-dependent IFN-gamma production. J Immunol. 2005; 175(3):1636-42. DOI: 10.4049/jimmunol.175.3.1636. View

Hayakawa K, Mitsuhashi N, Saito Y, Takahashi M, Katano S, Shiojima K . Effect of krestin (PSK) as adjuvant treatment on the prognosis after radical radiotherapy in patients with non-small cell lung cancer. Anticancer Res. 1993; 13(5C):1815-20. View

10.

Stagg J, Loi S, Divisekera U, Ngiow S, Duret H, Yagita H . Anti-ErbB-2 mAb therapy requires type I and II interferons and synergizes with anti-PD-1 or anti-CD137 mAb therapy. Proc Natl Acad Sci U S A. 2011; 108(17):7142-7. PMC: 3084100. DOI: 10.1073/pnas.1016569108. View

11.

Roda J, Parihar R, Lehman A, Mani A, Tridandapani S, Carson 3rd W . Interleukin-21 enhances NK cell activation in response to antibody-coated targets. J Immunol. 2006; 177(1):120-9. DOI: 10.4049/jimmunol.177.1.120. View

12.

Moreno M, Mol B, von Mensdorff-Pouilly S, Verheijen R, von Blomberg B, van den Eertwegh A . Toll-like receptor agonists and invariant natural killer T-cells enhance antibody-dependent cell-mediated cytotoxicity (ADCC). Cancer Lett. 2008; 272(1):70-6. DOI: 10.1016/j.canlet.2008.06.028. View

13.

Lu H, Yang Y, Gad E, Wenner C, Chang A, Larson E . Polysaccharide krestin is a novel TLR2 agonist that mediates inhibition of tumor growth via stimulation of CD8 T cells and NK cells. Clin Cancer Res. 2010; 17(1):67-76. PMC: 3017241. DOI: 10.1158/1078-0432.CCR-10-1763. View

14.

Zamai L, Ponti C, Mirandola P, Gobbi G, Papa S, Galeotti L . NK cells and cancer. J Immunol. 2007; 178(7):4011-6. DOI: 10.4049/jimmunol.178.7.4011. View

15.

Kono K, Takahashi A, Ichihara F, Sugai H, Fujii H, Matsumoto Y . Impaired antibody-dependent cellular cytotoxicity mediated by herceptin in patients with gastric cancer. Cancer Res. 2002; 62(20):5813-7. View

16.

Clynes R, Towers T, Presta L, Ravetch J . Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets. Nat Med. 2000; 6(4):443-6. DOI: 10.1038/74704. View

17.

Schmidt K, Leung B, Kwong M, Zarember K, Satyal S, Navas T . APC-independent activation of NK cells by the Toll-like receptor 3 agonist double-stranded RNA. J Immunol. 2003; 172(1):138-43. DOI: 10.4049/jimmunol.172.1.138. View

18.

Lee J, Lee K, Kim D, Heo D . Elevated TGF-beta1 secretion and down-modulation of NKG2D underlies impaired NK cytotoxicity in cancer patients. J Immunol. 2004; 172(12):7335-40. DOI: 10.4049/jimmunol.172.12.7335. View

19.

Ebihara T, Azuma M, Oshiumi H, Kasamatsu J, Iwabuchi K, Matsumoto K . Identification of a polyI:C-inducible membrane protein that participates in dendritic cell-mediated natural killer cell activation. J Exp Med. 2010; 207(12):2675-87. PMC: 2989763. DOI: 10.1084/jem.20091573. View

20.

Nakazato H, Koike A, Saji S, Ogawa N, Sakamoto J . Efficacy of immunochemotherapy as adjuvant treatment after curative resection of gastric cancer. Study Group of Immunochemotherapy with PSK for Gastric Cancer. Lancet. 1994; 343(8906):1122-6. DOI: 10.1016/s0140-6736(94)90233-x. View