Olfactory ecto-mesenchymal stem cells (OE-MSCs) are a novel population of resident stem cells in the olfactory lamina propria with strong immunosuppressive function. Exosomes released by MSCs are considered to carry various mRNAs, microRNAs and proteins from cells and function as an extension of MSCs. However, it remains unclear whether exosomes derived from OE-MSCs (OE-MSCs-Exos) possess any immunoregulatory functions. In this study, we found that OE-MSCs-Exos possessed strong suppressive function in CD4⁺T cell proliferation, accompanied by reduced IL-17, IFN-γ and enhanced TGF-β, IL-10 secreted by T cells. In experimental colitis mice, treatment of OE-MSCs-Exos markedly alleviated the severity of disease, and Th1/Th17 subpopulations were remarkably reduced whereas Treg cells were increased after OE-MSCs-Exos treatment. Mechanistically, OE-MSCs-Exos were demonstrated to inhibit the differentiation of Th1 and Th17 cells, but promote the induction of Treg cells in vitro. Taken together, our findings identified a novel function of OE-MSCs-Exos in regulating T-cell responses, indicating that OE-MSCs-Exos may represent a new cell-free therapy for the treatment of IBD and other inflammatory diseases.

Metformin, an oral medicine broadly used for the treatment of type 2 diabetes, has been found to significantly improve tumor incidence and survival in large-scale clinical analysis. In recent years, the antitumor effect and mechanism of metformin have received much attention. Myeloid-derived suppressor cells (MDSCs), a major immunosuppressive cell type that accumulates in tumor-bearing hosts, can inhibit T cells and promote tumor immune escape. The mechanism by which metformin exerts its anti-tumor effect by regulating MDSCs remains unclear. Here, we found that metformin could inhibit the accumulation and suppressive capacity of G-MDSCs, delay tumor progression and elicit Th1 and CTL responses in murine colon cancer CT-26 cell-transplanted mice. In additionally, metformin could enhance the phosphorylation of AMPK, reduce STAT3 phosphorylation levels, and down-regulate the inhibitory function of G-MDSCs in vitro. These results suggest that metformin may be a potential clinical benefit for antitumor immunotherapy in tumor-bearing mice.

Myeloid-derived suppressive cells (MDSC) inhibit antitumor immunity and confer a survival advantage for tumor evasion. Tumor cells also support MDSC expansion and recruitment by secreting multiple growth factors and cytokines, but the mechanisms by which tumors affect MDSC function are not completely understood. Here, we found that the neuronal guidance protein netrin-1 was selectively secreted by MC38 murine colon cancer cells, which could enhance the immunosuppressive activity of MDSCs. MDSCs predominantly expressed one type of netrin-1 receptor, adenosine receptor 2B (A2BR). Netrin-1 interacted with A2BR on MDSCs to activate the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling pathway, which ultimately increased CREB phosphorylation in MDSCs. Furthermore, netrin-1 knockdown in tumor cells inhibited the immunosuppressive activity of MDSCs and restored antitumor immunity in MC38 tumor xenograft mice. Intriguingly, high netrin-1 in the plasma correlated with MDSCs in patients with colorectal cancer. In conclusion, netrin-1 significantly enhanced the immunosuppressive function of MDSCs through A2BR on MDSCs, thus promoting the development of tumors. These findings highlight that netrin-1 may regulate the abnormal immune response in colorectal cancer and may become a potential target for immunotherapy.