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

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.