Melatonin enhances anti-tumor immunity by targeting macrophages PD-L1 via exosomes derived from gastric cancer cells.

Melatonin (MLT) is a hormone with potential anti-tumor properties, but the molecular mechanisms remain unclear. The present study aimed to explore the effect of MLT on exosomes derived from gastric cancer cells, with the goal of gaining insight into its anti-tumor activity. Results from in vitro experiments showed that MLT was able to enhance the anti-tumor activity of macrophages that had been suppressed by exosomes from gastric cancer cells. This effect was achieved through regulation of the levels of PD-L1 in macrophages via modulation of the associated microRNAs in the cancer-derived exosomes. Furthermore, MLT treatment increased the secretion of TNF-α and CXCL10 by the macrophages. Besides, MLT treatment of gastric cancer cells led to the production of exosomes that promoted the recruitment of CD8+ T cells to the tumor site, resulting in inhibition of tumor growth. Collectively, these results provide evidence for the modulation of the tumor immune microenvironment by MLT through regulation of exosomes derived from gastric cancer cells, suggesting a potential role for MLT in novel anti-tumor immunotherapies.

RNA-Seq approach to investigate the effects of melatonin on bone marrow-derived dendritic cells from dextran sodium sulfate-induced colitis mice.

Melatonin (MLT) was reported to have therapeutic effects on inflammatory bowel disease (IBD) such as ulcerative colitis (UC) and Crohn's disease (CD) due to its anti-inflammatory and immunomodulatory properties. However, whether the beneficial effects of melatonin on colitis are through altering the immune response of bone marrow-derived dendritic cells (BMDCs) has not been well characterized. Here, we propose that MLT alleviates dextran sulfate sodium (DSS)-induced colitis in mice through its regulation of the immune response of BMDCs, in which some lncRNA, circRNA, miRNA, and mRNA may be involved. We at first established a DSS-induced colitis mouse model and found that the concentration of MLT in the serum of DSS-induced colitis mice was significantly lower than that in the control mice. Supplementation with MLT alleviated DSS-induced colitis in mice, which was reflected by preventing mouse body weight loss, colon length shortening, inflammation, and epithelial tissue destruction and abscission in the colon. We then isolated and cultured BMDCs and found that MLT could inhibit the activation of BMDCs from the colitis mice, which was reflected by reducing the phagocytotic ability of the cells, inhibiting their migration, and decreasing their secretion of pro-inflammatory cytokines. RNA sequencing results showed that MLT promoted the transformation of BMDCs into immune tolerant phenotypes in DSS-induced colitis mice through affecting non-coding RNAs (ncRNAs). Among them, lncRNA ENSMUST00000226323, circRNA-0520, and circRNA-2243 were predicted to interact with miRNA-709, and mRNAs of Ywhaz and Ccl9 were the targets of miRNA-709, all of which were involved in MLT-induced alteration of BMDCs functions in DSS-induced colitis mice via PI3K-Akt pathway. Our findings may provide some clues for understanding MLT inhibiting inflammatory response in DSS-induced colitis, which may be through alteration of BMDCs function.