title: Polysaccharide Agaricus blazei Murill stimulates myeloid derived suppressor cell differentiation from M2 to M1 type, which mediates inhibition of tumour immune-evasion via the Toll-like receptor 2 pathway.
abstract: Gr-1(+) CD11b(+) myeloid-derived suppressor cells (MDSCs) accumulate in tumor-bearing animals and play a critical negative role during tumor immunotherapy. Strategies for inhibition of MDSCs are expected to improve cancer immunotherapy. Polysaccharide Agaricus blazei Murill (pAbM) has been found to have anti-cancer activity, but the underlying mechanism of this is poorly understood. Here, pAbM directly activated the purified MDSCs through inducing the expression of interleukin-6 (IL-6), IL-12, tumour necrosis factor and inducible nitric oxide synthase (iNOS), CD86, MHC II, and pSTAT1 of it, and only affected natural killer and T cells in the presence of Gr-1(+) CD11b(+) monocytic MDSCs. On further analysis, we demonstrated that pAbM could selectively block the Toll-like receptor 2 (TLR2) signal of Gr-1(+) CD11b(+) MDSCs and increased their M1-type macrophage characteristics, such as producing IL-12, lowering expression of Arginase 1 and increasing expression of iNOS. Extensive study showed that Gr-1(+) CD11b(+) MDSCs by pAbM treatment had less ability to convert the CD4(+) CD25(-) cells into CD4(+) CD25(+) phenotype. Moreover, result from selective depletion of specific cell populations in xenograft mice model suggested that the anti-tumour effect of pAbM was dependent on Gr-1(+ ) CD11b(+) monocytes, nether CD8(+) T cells nor CD4(+) T cells. In addition to, pAbM did not inhibit tumour growth in TLR2(-/-) mice. All together, these results suggested that pAbM, a natural product commonly used for cancer treatment, was a specific TLR2 agonist and had potent anti-tumour effects through the opposite of the suppressive function of Gr-1(+) CD11b(+) MDSCs.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, China.|Department of Obsterics and Gynaecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Oncology, XiangYang Central Hospital, Hubei University of Arts and Science, XiangYang, China.
authors.forename: Lingyun
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Ophthalmology, Renmin Hospital of Wuhan University, Wuhan, China.
authors.forename: Xiangxiang
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of Oncology, XiangYang Central Hospital, Hubei University of Arts and Science, XiangYang, China.
authors.forename: Yuehua
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Cardiology, XiangYang Central Hospital, Hubei University of Arts and Science, XiangYang, China.
authors.forename: WenWei
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Oncology, XiangYang Central Hospital, Hubei University of Arts and Science, XiangYang, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Gong
mesh_terms: D000284:Administration, Oral; D000364:Agaricus / Q000276:immunology*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D039481:CD11b Antigen / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D005260:Female; D062610:Fungal Polysaccharides / Q000008:administration & dosage / Q000276:immunology* / Q000494:pharmacology*; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D022423:Myeloid Cells / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D019707:Receptors, Chemokine / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000819:agonists* / Q000172:deficiency / Q000235:genetics; D019139:Tumor Escape / Q000187:drug effects / Q000276:immunology*; D059016:Tumor Microenvironment / Q000187:drug effects / Q000276:immunology
chemical_list: D000970:Antineoplastic Agents; D039481:CD11b Antigen; D062610:Fungal Polysaccharides; C503133:Gr-1 protein, mouse; D019707:Receptors, Chemokine; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2
keywords: Toll-like receptor-2; myeloid derived suppressor cells; polysaccharide Agaricus blazei Murill