Polysaccharide Krestin is a Novel TLR2 Agonist That Mediates Inhibition of Tumor Growth Via Stimulation of CD8 T Cells and NK Cells

Overview

Journal Clin Cancer Res

Specialty Oncology

Date 2010 Nov 12

PMID 21068144

Citations 59

Authors

Hailing Lu

Yi Yang

Ekram Gad

Cynthia A Wenner

Amy Chang

Emily R Larson

Yushe Dang

Mark Martzen

Leanna J Standish

Mary L Disis

Affiliations

Soon will be listed here.

Abstract

Purpose: Polysaccharide krestin (PSK) is a mushroom extract that has been long used in Asia and recently in Western countries as a treatment for cancer due to its presumed immune potentiating effects. Although there have been reports of clinical responses after patients have ingested PSK, the mechanism of action of the agent remains undefined. The current study was undertaken to investigate the mechanism of the antitumor actions of PSK.

Experimental Design: The immunostimulatory effect of PSK was first evaluated in vitro using splenocytes from neu transgenic mice and Toll-like receptor (TLR) 2 knockout (TLR2(-/-)) mice. Then the immunostimualtory and antitumor effect of PSK was determined using tumor-bearing neu transgenic mice, TLR2(-/-), and wild-type C57BL/6 mice.

Results: We demonstrate that PSK is a selective TLR2 agonist, and the activation of dendritic cells (DC) and T cells by PSK is dependent on TLR2. Oral administration of PSK in neu transgenic mice significantly inhibits breast cancer growth. Selective depletion of specific cell populations suggests that the antitumor effect of PSK is dependent on both CD8(+) T cell and NK cells, but not CD4(+) T cells. PSK does not inhibit tumor growth in TLR2(-/-) mice suggesting that the antitumor effect is mediated by TLR2.

Conclusion: These results demonstrate that PSK, a natural product commonly used for the treatment of cancer, is a specific TLR2 agonist and has potent antitumor effects via stimulation of both innate and adaptive immune pathways.

Citing Articles

Polysaccharide Fraction Isolated from Exhibits Anti-Cancer Effects Through Immunostimulating Activities.

Park M, Son S, Kim T, Shim S, Jang B, Park S Mar Drugs. 2025; 23(1).

PMID: 39852540 PMC: 11766681. DOI: 10.3390/md23010038.

Identification and Analysis of Anticancer Therapeutic Targets from the Polysaccharide Krestin (PSK) and Polysaccharopeptide (PSP) Using Inverse Docking.

Lopez-Gil C, Tellez-Jurado A, Velasco-Velazquez M, Anducho-Reyes M Molecules. 2024; 29(22).

PMID: 39598781 PMC: 11596896. DOI: 10.3390/molecules29225390.

Integration of single-cell sequencing and drug sensitivity profiling reveals an 11-gene prognostic model for liver cancer.

Zhou Q, Wu J, Bei J, Zhai Z, Chen X, Liang W Hum Genomics. 2024; 18(1):132.

PMID: 39587687 PMC: 11590408. DOI: 10.1186/s40246-024-00698-2.

The role of macrophage plasticity in neurodegenerative diseases.

Ma H, Zhu M, Chen M, Li X, Feng X Biomark Res. 2024; 12(1):81.

PMID: 39135084 PMC: 11321226. DOI: 10.1186/s40364-024-00624-7.

The Role of the Toll-like Receptor 2 and the cGAS-STING Pathways in Breast Cancer: Friends or Foes?.

Cossu C, Di Lorenzo A, Fiorilla I, Todesco A, Audrito V, Conti L Int J Mol Sci. 2024; 25(1).

PMID: 38203626 PMC: 10778705. DOI: 10.3390/ijms25010456.

References

Xu S, Koldovsky U, Xu M, Wang D, Fitzpatrick E, Son G . High-avidity antitumor T-cell generation by toll receptor 8-primed, myeloid- derived dendritic cells is mediated by IL-12 production. Surgery. 2006; 140(2):170-8. DOI: 10.1016/j.surg.2006.03.006. View

Asprodites N, Zheng L, Geng D, Velasco-Gonzalez C, Sanchez-Perez L, Davila E . Engagement of Toll-like receptor-2 on cytotoxic T-lymphocytes occurs in vivo and augments antitumor activity. FASEB J. 2008; 22(10):3628-37. PMC: 2537425. DOI: 10.1096/fj.08-108274. View

Hirai R, Oguchi Y, Sugita N, Matsunaga K, Nomoto K . Enhancement of T-cell proliferation by PSK. Int J Immunopharmacol. 1993; 15(6):745-50. DOI: 10.1016/0192-0561(93)90147-q. View

Gerosa F, Baldani-Guerra B, Nisii C, Marchesini V, Carra G, Trinchieri G . Reciprocal activating interaction between natural killer cells and dendritic cells. J Exp Med. 2002; 195(3):327-33. PMC: 2193595. DOI: 10.1084/jem.20010938. View

Zhang X, Munegowda M, Yuan J, Wei Y, Xiang J . Optimal TLR9 signal converts tolerogenic CD4-8- DCs into immunogenic ones capable of stimulating antitumor immunity via activating CD4+ Th1/Th17 and NK cell responses. J Leukoc Biol. 2010; 88(2):393-403. DOI: 10.1189/jlb.0909633. View

Krieg A . Therapeutic potential of Toll-like receptor 9 activation. Nat Rev Drug Discov. 2006; 5(6):471-84. DOI: 10.1038/nrd2059. 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

Kryczek I, Banerjee M, Cheng P, Vatan L, Szeliga W, Wei S . Phenotype, distribution, generation, and functional and clinical relevance of Th17 cells in the human tumor environments. Blood. 2009; 114(6):1141-9. PMC: 2723011. DOI: 10.1182/blood-2009-03-208249. View

Kato M, Hirose K, Hakozaki M, Ohno M, Saito Y, Izutani R . Induction of gene expression for immunomodulating cytokines in peripheral blood mononuclear cells in response to orally administered PSK, an immunomodulating protein-bound polysaccharide. Cancer Immunol Immunother. 1995; 40(3):152-6. PMC: 11037764. DOI: 10.1007/BF01517346. View

10.

EISENBERG D, Davis R, Ettner S, Appel S, Wilkey S, Van Rompay M . Trends in alternative medicine use in the United States, 1990-1997: results of a follow-up national survey. JAMA. 1998; 280(18):1569-75. DOI: 10.1001/jama.280.18.1569. View

11.

Bryant J, Day R, Whiteside T, Herberman R . Calculation of lytic units for the expression of cell-mediated cytotoxicity. J Immunol Methods. 1992; 146(1):91-103. DOI: 10.1016/0022-1759(92)90052-u. 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.

Richardson M, Sanders T, Palmer J, Greisinger A, Singletary S . Complementary/alternative medicine use in a comprehensive cancer center and the implications for oncology. J Clin Oncol. 2000; 18(13):2505-14. DOI: 10.1200/JCO.2000.18.13.2505. View

14.

Harada M, Matsunaga K, Oguchi Y, Iijima H, Tamada K, Abe K . Oral administration of PSK can improve the impaired anti-tumor CD4+ T-cell response in gut-associated lymphoid tissue (GALT) of specific-pathogen-free mice. Int J Cancer. 1997; 70(3):362-72. DOI: 10.1002/(sici)1097-0215(19970127)70:3<362::aid-ijc19>3.0.co;2-h. View

15.

Saijo S, Fujikado N, Furuta T, Chung S, Kotaki H, Seki K . Dectin-1 is required for host defense against Pneumocystis carinii but not against Candida albicans. Nat Immunol. 2006; 8(1):39-46. DOI: 10.1038/ni1425. View

16.

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

17.

Sakamoto J, Morita S, Oba K, Matsui T, Kobayashi M, Nakazato H . Efficacy of adjuvant immunochemotherapy with polysaccharide K for patients with curatively resected colorectal cancer: a meta-analysis of centrally randomized controlled clinical trials. Cancer Immunol Immunother. 2005; 55(4):404-11. PMC: 11030578. DOI: 10.1007/s00262-005-0054-1. View

18.

Pandey S, Agrawal D . Immunobiology of Toll-like receptors: emerging trends. Immunol Cell Biol. 2006; 84(4):333-41. DOI: 10.1111/j.1440-1711.2006.01444.x. View

19.

Liu H, Komai-Koma M, Xu D, Liew F . Toll-like receptor 2 signaling modulates the functions of CD4+ CD25+ regulatory T cells. Proc Natl Acad Sci U S A. 2006; 103(18):7048-53. PMC: 1444884. DOI: 10.1073/pnas.0601554103. View

20.

Rakoff-Nahoum S, Medzhitov R . Toll-like receptors and cancer. Nat Rev Cancer. 2008; 9(1):57-63. DOI: 10.1038/nrc2541. View