Soluble β-glucan from Grifola frondosa induces tumor regression in synergy with TLR9 agonist via dendritic cell-mediated immunity

J Leukoc Biol. 2015 Dec;98(6):1015-25. doi: 10.1189/jlb.1A0814-415RR. Epub 2015 Aug 21.


The maturation of dendritic cells into more-immunostimulatory dendritic cells by stimulation with different combinations of immunologic agents is expected to provide efficient, adoptive immunotherapy against cancer. Soluble β-glucan maitake D-fraction, extracted from the maitake mushroom Grifola frondosa, acts as a potent immunotherapeutic agent, eliciting innate and adoptive immune responses, thereby contributing to its antitumor activity. Here, we evaluated the efficacy of maitake D-fraction, in combination with a Toll-like receptor agonist, to treat tumors in a murine model. Our results showed that maitake D-fraction, in combination with the Toll-like receptor 9 agonist, cytosine-phosphate-guanine oligodeoxynucleotide, synergistically increased the expression of dendritic cell maturation markers and interleukin-12 production in dendritic cells, but it did not increase interleukin-10 production, generating strong effector dendritic cells with an augmented capacity for efficiently priming an antigen-specific, T helper 1-type T cell response. Maitake D-fraction enhances cytosine-phosphate-guanine oligodeoxynucleotide-induced dendritic cell maturation and cytokine responses in a dectin-1-dependent pathway. We further showed that a combination therapy using cytosine-phosphate-guanine oligodeoxynucleotide and maitake D-fraction was highly effective, either as adjuvants for dendritic cell vaccination or by direct administration against murine tumor. Therapeutic responses to direct administration were associated with increased CD11c(+) dendritic cells in the tumor site and the induction of interferon-γ-producing CD4(+) and CD8(+) T cells. Our results indicate that maitake D-fraction and cytosine-phosphate-guanine oligodeoxynucleotide synergistically activated dendritic cells, resulting in tumor regression via an antitumor T helper cell 1-type response. Our findings provide the basis for a potent antitumor therapy using a novel combination of immunologic agents for future clinical immunotherapy studies in patients.

Keywords: CpG ODN; dectin-1; immunotherapy; maitake.

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / pathology
  • Dendritic Cells / immunology*
  • Dendritic Cells / pathology
  • Drug Synergism
  • Female
  • Grifola / chemistry*
  • Immunity, Cellular / drug effects*
  • Interferon-gamma / immunology
  • Interleukin-10 / immunology
  • Interleukin-12 / immunology
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Neoplasms, Experimental* / drug therapy
  • Neoplasms, Experimental* / immunology
  • Neoplasms, Experimental* / pathology
  • Oligodeoxyribonucleotides / agonists
  • Oligodeoxyribonucleotides / pharmacology*
  • Th1 Cells / immunology
  • Th1 Cells / pathology
  • Toll-Like Receptor 9 / agonists*
  • Toll-Like Receptor 9 / immunology
  • beta-Glucans / agonists
  • beta-Glucans / chemistry
  • beta-Glucans / pharmacology*


  • CPG-oligonucleotide
  • IL10 protein, mouse
  • Oligodeoxyribonucleotides
  • Tlr9 protein, mouse
  • Toll-Like Receptor 9
  • beta-Glucans
  • Interleukin-10
  • Interleukin-12
  • Interferon-gamma