Yeast-Derived Particulate ß-Glucan Treatment Subverts the Suppression of Myeloid-Derived Suppressor Cells (MDSC) by Inducing Polymorphonuclear MDSC Apoptosis and Monocytic MDSC Differentiation to APC in Cancer.

Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature myeloid cells that promote tumor progression. In this study, we demonstrated that activation of a C-type lectin receptor, dectin-1, in MDSC differentially modulates the function of different MDSC subsets. Yeast-derived whole ß-glucan particles (WGP; a ligand to engage and activate dectin-1, oral treatment in vivo) significantly decreased tumor weight and splenomegaly in tumor-bearing mice with reduced accumulation of polymorphonuclear MDSC but not monocytic MDSC (M-MDSC), and decreased polymorphonuclear MDSC suppression in vitro through the induction of respiratory burst and apoptosis. On a different axis, WGP-treated M-MDSC differentiated into F4/80(+)CD11c(+) cells in vitro that served as potent APC to induce Ag-specific CD4(+) and CD8(+) T cell responses in a dectin-1-dependent manner. Additionally, Erk1/2 phosphorylation was required for the acquisition of APC properties in M-MDSC. Moreover, WGP-treated M-MDSC differentiated into CD11c(+) cells in vivo with high MHC class II expression and induced decreased tumor burden when inoculated s.c. with Lewis lung carcinoma cells. This effect was dependent on the dectin-1 receptor. Strikingly, patients with non-small cell lung carcinoma that had received WGP treatment for 10-14 d prior to any other treatment had a decreased frequency of CD14(-)HLA-DR(-)CD11b(+)CD33(+) MDSC in the peripheral blood. Overall, these data indicate that WGP may be a potent immune modulator of MDSC suppressive function and differentiation in cancer.

The effects of ß-glucans on dendritic cells and implications for cancer therapy.

ß-Glucans are polysaccharides of ß-D-glucose extracted from the cell walls of different species of mushrooms, yeast, oat, barley, seaweeds, algae and bacteria. Modern biomedical research has identified ß-glucans as biological response modifiers (BRM) with anti-tumor properties that elicit potent immune responses through their recognition by a variety of pattern recognition receptors (PRRs) on dendritic cells (DCs), macrophages and neutrophils. Complement receptor-3 (CR3), lactosylceramides, scavenger receptors and dectin-1 are involved in ß-glucan recognition, triggering a series of signaling events that modulate innate and subsequently adaptive immune responses. ß-Glucan binding to specific receptors in DCs and macrophages triggers their activation and maturation, increases their antigen-presentation ability and enhances the production of proinflammatory cytokines that stimulate the polarization of TH1 or TH17 responses, and induces the activation of antigen-specific CD8+ cytotoxic T lymphocytes (CTL). Moreover, large ß-glucans can be degraded by macrophages into smaller moieties, when released, prime CR3 receptor on neutrophils and natural killer (NK) cells mediating CR3-dependent cellular cytotoxicity (CR3-DCC) of iC3b opsonized tumor cells. Elucidating the molecular mechanisms of ß- glucan-induced signaling in immune cells is essential for the design of new therapeutic strategies against cancer. Future studies should be done to translate ß-glucan research to the clinic.