Exosomal miR-208b related with oxaliplatin resistance promotes Treg expansion in colorectal cancer

Oxaliplatin resistance is a challenge in the treatment of colorectal cancer (CRC) patients. Regulatory T cells (Tregs) are well known for their immunosuppressive roles, and targeting Tregs is an effective way to improve chemosensitivity. Exosome-delivered microRNA (miRNA) might be used as a potential biomarker for predicting chemosensitivity. However, the relationship between Tregs and exosomal miRNAs remains largely unknown. TaqMan low-density array was performed to screen the differentially expressed serum miRNAs from pooled serum of patients who had FOLFOX treatment. Differential expression was validated using qRT-PCR in individual samples. Exosomes were isolated by sequential differential centrifugation, and they were verified by transmission electron microscopy. The RNA and protein levels were determined by quantitative realtime PCR and western blotting. A mouse xenograft model was adopted to evaluate the correlation between exosome-derived miR-208b and Tregs in vivo. We demonstrated that circulating miR-208b is a non-invasive marker for predicting FOLFOX sensitivity in CRC. miR-208b in colon cancer was secreted by tumor cells in the pattern of exosomes, and oxaliplatin-resistant cells showed the most obvious phenomenon of miR-208b increase. Colon cancer cell-secreted miR-208b was sufficiently delivered into recipient T cells to promote Treg expansion by targeting programmed cell death factor 4 (PDCD4). Furthermore, in vivo studies indicated that Treg expansion mediated by cancer cell-secreted miR-208b resulted in tumor growth and oxaliplatin resistance. Our results demonstrate that tumor-secreted miR-208b promotes Treg expansion by targeting PDCD4, and it may be related to a decrease of oxaliplatin-based chemosensitivity in CRC. These findings highlight a potential role of exosomal miR-208b as a predictive biomarker for oxaliplatin-based therapy response, and they provide a novel target for immunotherapy.