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.

KEYWORDS:

• antitumor immunity
• immune modulator
• macrophage
• melanoma
• Oat β-glucan

Conflict of interest statement

The authors do not have any conflict of interest to declare.

Acknowledgment

This work is supported by funding from the VeloSano Cancer Research Award (M.Z. and J.A.K.). This work is supported by funding from the National Cancer Institute (R21CA181875 and R21CA218790 to AYH), the St. Baldrick's Foundation, the Alex's Lemonade Stand Foundation, Hyundai Hope-on-Wheels Program, Pediatric Cancer Research Foundation, the Steven G. AYA Cancer Research Fund, Samuel Szabo Foundation, Keira Kilbane Cancer Discovery Fund, Erroll's Cancer Discovery Fund, and the Theresia G. & Stuart F. Kline Family Foundation.