2-methylpyridine-1-ium-1-sulfonate modifies tumor-derived exosome mediated macrophage polarization: Relevance to the tumor microenvironment

The compound "2-methylpyridine-1-ium-1-sulfonate" (MPS) is the active constituent of Allium hirtifolium Boiss. bulbs with potent anti-angiogenic and anti-cancer activities. Tumor microenvironment (TME) plays a key role in tumor progression via tumor derived exosome (TEX) mediated polarization of M2 type tumor associated macrophages (TAMs). In this study, we explored direct and colorectal cancer (CRC) exosome-mediated impacts of MPS on macrophage polarization to find out whether MPS could modify TEX in favor of anti-tumor M1-like macrophage polarization. After MPS isolation and characterization, first its direct anti-cancer effects were evaluated on HT-29 cells. Then, TEX were isolated from untreated (C-TEX) and MPS-treated (MPS-TEX) HT-29 cells. THP-1 M0 macrophages were incubated with MPS, C-TEX and MPS-TEX. Macrophage polarization was evaluated by flow cytometry, ELISA and gene expression analysis of several M1- and M2-related markers. MPS induced apoptosis and cell cycle arrest and reduced the migration ability of HT-29 cells. C-TEX polarized M0 macrophages toward a mixed M1-/M2-like phenotype with a high predominance of M2-like cells. Macrophage treatment with MPS was associated with the induction of M1-like phenotype. Also, MPS was demonstrated to ameliorate TEX-mediated effects in favor of M1-like polarization. In conclusion, our study addresses for the first time, the potential capability of MPS in skewing macrophages toward an anti-cancer M1-like phenotype both directly and in a TEX-dependent manner. Thus, in addition to its direct anti-cancer effects, this compound could also modify TME in favor of tumor eradication via its direct and TEX-mediated effects on macrophage polarization as a novel anti-cancer mechanism.