TLR2 Signaling Promoted Tumor Development through Enhancing Inflammation and Regulatory T cells to Suppress Anti-Tumor Immunity

Abstract

Abstract Inflammation is a relevant physiologic process necessary for immune protection, tissue repair and remodeling. However, chronic inflammation is known to contribute tumor development, including tumor initiation, promotion and progression. Recent studies have shown that up-regulation of Toll-like receptors (TLRs) in tumor microenvironment induced the inflammatory responses. Here, we hypothesized that the TLR2 signaling within tumor microenvironment elicits an inflammatory response and such facilitates tumor development. A murine B16F10 melanoma model was utilized to investigate the role of endogenous TLR2 signaling in tumor development. Anti-tumor immunity and the presence of tumor-associated inflammatory mediators were analyzed by flow cytometry and ELISA in the TLR2 knockout (TLR2 KO) and wild-type (WT) tumor-bearing animals. When compared to the TLR2 deficient mice, WT mice had a significantly aggressive-appearing pathology, such as elicited tumor growth and metastasis. When the splenocytes cultured with tumor-conditional medium, WT produced elevated levels of pro-inflammatory cytokines, whereas TLR2KO or the WT receiving anti-TLR2 antibody treatment blocked the inflamed-like phenomenon and consequently showed a better anti-tumor IFN-γ response. Additionally, tumors from WT mice exhibited comparably higher infiltration levels of CD4+CD25+Foxp3+ regulatory T cells, but much less CD8+ T cells. These results support that cancer cells-derived components through TLR2 signaling generate an inflammatory microenvironment hospitable for tumor growth, and it indicates TLR2 as a potential therapeutic target for cancer immunotherapy.