LBP3 promotes the production of SCFAs to inhibit PMN-MDSC function and exert anti-tumor effects

Objective The aim of this study is to explore the potential of LBP3 in modulating polymorphonuclear myeloid-derived suppressor cells to exert anti-tumor effects and to investigate whether this mechanism is mediated by short-chain fatty acids.Methods A subcutaneous H22 liver cancer model was employed to assess the antitumor activity of LBP3 and its regulatory effects on PMN-MDSC. Mixed antibiotics were used to disrupt gut microbiota in some groups, and fecal microbiota transplantation was conducted to explore the immune regulatory role of LBP3-modulated flora. SCFAs levels from Serum in tumor-bearing mice were quantified using liquid chromatography-mass spectrometry, and the effect of butyrate on arginase 1 (Arg-1) expression was evaluated in vitro.Results Treatment with both low-dose (125 mg/kg) and high-dose (250 mg/kg) LBP3 significantly inhibited tumor growth in H22 tumor-bearing mice. This treatment also led to a marked reduction in the proportion of PMN-MDSC in both the spleen and tumor, a decrease in Arg-1 levels within the tumor, and a reduced proportion of Treg cells in lymphoid tissues. Additionally, the infiltration of CD8+T cells into the tumor was significantly enhanced. However, these effects were reversed upon antibiotic treatment , suggesting a crucial role for the gut microbiota. The therapeutic group receiving LBP3-mediated fecal microbiota transplantation was able to reproduce these effects, confirming the involvement of a microbiota-dependent mechanism. Furthermore, co-expression of Ly6G and GPR43 in the tumor was also observed. LBP3 treatment resulted in increased levels of SCFAs, particularly butyrate, in both blood and tumor tissues. In vitro, butyrate was shown to inhibit Arg-1 expression in MSC-2 cells, further supporting the hypothesis that SCFAs mediate the immune-modulatory effects of LBP3.Conclusion LBP3 exerts its anti-tumor effects by promoting short-chain fatty acid (SCFA) production, which subsequently inhibits the function of PMN-MDSC. This highlights LBP3's potential as an immunomodulatory agent in cancer therapy.