Systemic administration of β-glucan of 200 kDa modulates melanoma microenvironment and suppresses metastatic cancer

Abstract

Converting an immunosuppressive melanoma microenvironment into one that favors the induction of antitumor immunity is indispensable for effective cancer immunotherapy. In the current study we demonstrate that oat-derived β-(1-3)-(1-4)-glucan of 200 kDa molecular size (BG34-200) previously shown to mediate direct interaction with macrophages could alter the immune signature within melanoma microenvironment. Systemic administration of BG34-200 resulted in reversion of tolerant melanoma microenvironment to an immunogenic one that allows M1-type activation of macrophages, the induction of pro-inflammatory cytokines/chemokines including IFN-γ, TNF-α, CXCL9, and CXCL10, and enhanced IRF1 and PD-L1 expression. In turn, BG34-200 induced a superior antitumor response against primary and lung metastatic B16F10 melanoma compared to untreated controls. The enhanced tumor destruction was accompanied with significantly increased tumor infiltration of CD4 and CD8 T cells as well as elevated IFN-γ in the tumor sites. Systemic administration of BG34-200 also provoked systemic activation of tumor draining lymph node T cells that recognize antigens naturally expressing in melanoma (gp100/PMEL). Mechanistic studies using CD11b-knockout (KO), CD11 c-DTR transgenic mice and nude mice revealed that macrophages, DCs, T cells and NK cells were all required for the BG34-200-induced therapeutic benefit. Studies using IFN-γ-KO transgenic mice showed that IFN-γ was essential for the BG34-200-elicited antitumor response. Beyond melanoma, the therapeutic efficacy of BG34-200 and its immune stimulating activity were demonstrated in a mouse model of osteosarcoma. Together, BG34-200 is highly effective in modulating antitumor immunity. Our data support the potential therapeutic use of this novel immune modulator in the treatment of metastatic melanoma.

Ferumoxytol-β-glucan Inhibits Melanoma Growth via Interacting with Dectin-1 to Polarize Macrophages into M1 Phenotype

“…By binding to these receptors, β-glucan exerts its immunomodulating effects to defend against infection and prevent tumor growth by activating various immune cells (macrophages, T cells, natural killer cells, etc.) 70 , 71 . Consistent with these studies, we found that solo treatment with β-glucan could indirectly inhibit B16F10 cell growth by skewing macrophages toward an M1 phenotype through activating MAPK and NF-κB signaling.…”

Optimizing Tumor Microenvironment for Cancer Immunotherapy: β-Glucan-Based Nanoparticles

“…BG34-induced alteration in TME and LN immune signatures resulted in regression of established primary and metastasis of B16F10 melanoma model in C57BL/6 mice. Such BG34-induced tumor regression was not observed in the CD11b KO mouse model ( 105 ). Results of these studies suggested that soluble BG34 glucans have a great potential to prime immune cells and enable them to mediate innate and adaptive antitumor immune responses.…”

“…β-glucans with different structures appear to stimulate antitumor responses in completely different manners, and these detailed molecular mechanisms need to be further investigated. In vivo administration of oat-derived BG34 glucan could stimulate production of pro-inflammatory cytokines in TME, and the protective immunity was associated with a significant reduction in tumor-infiltrated granulocytes ( 105 ). In contrast, in vivo administration of soluble yeast-derived BG36 glucan did not induce any pro-inflammatory cytokines in TME, and the protective immunity was associated with a significant increase of tumor-infiltrating neutrophils that are primed for CR3-DCC ( 98 ).…”

“…These observations suggested that CD11b-mediated effects are likely to be restricted to a specific stage in the macrophage vs. DC lineage differentiation process. Since multiple studies have demonstrated specific binding of BG34 ( 105 ) and BG36 ( 91 ) with CD11b, these observations provided strong rationale for investigating whether these glucans can specifically affect subtypes of CD11b + myeloid cells or a particular stage of the CD11b + macrophage vs. DC lineage differentiation process. Identification of β-glucans capable of promoting this specific differentiation pathway may lead to novel clinical applications in cancer and other immune-mediated diseases.…”

Cell-derived vesicles for delivery of cancer immunotherapy

“…On the cell wall of the outer layer of yeast, there are a large number of polysaccharides and proteins, such as β-glucan, chitosan, mannoprotein, and so on [144]. β-glucan, as the most abundant ingredient, can bind to Dectin-1 receptors on immune cells to cause a series of immune responses including phagocytosis [145][146][147]. Cell wall derived from yeast can be utilized as an adjuvant to activate APCs, and next induce immune responses.…”