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

Abstract

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.

• Authors: Yuki Masuda, Daiki Nawa, Yoshiaki Nakayama, Morichika Konishi, Hiroaki Nanba
• Journal: Journal of leukocyte biology (J Leukoc Biol) Vol. 98 Issue 6 Pg. 1015-25 (Dec 2015) ISSN: 1938-3673 [Electronic] United States
• PMID: 26297795 (Publication Type: Journal Article)
• Copyright: © Society for Leukocyte Biology.

Chemical References

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

Topics

• Animals
• CD8-Positive T-Lymphocytes (immunology, pathology)
• Dendritic Cells (immunology, 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, immunology, pathology)
• Oligodeoxyribonucleotides (agonists, pharmacology)
• Th1 Cells (immunology, pathology)
• Toll-Like Receptor 9 (agonists, immunology)
• beta-Glucans (agonists, chemistry, pharmacology)