MiR-15a/16-1 deficiency induces IL-10-producing CD19⁺ TIM-1⁺ cells in tumor microenvironment

IL-10-producing B cells (B10) are associated with autoimmune diseases, infection and tumours. MiR-15a/16 as a tumour-suppressive gene is down-regulated in several tumours, such as chronic lymphocytic leukaemia, pituitary adenomas and prostate carcinoma. Here, increased frequency of IL-10-producing CD19⁺ Tim-1⁺ cells was seen in both aged miR-15a/16^-/- mice (15-18 months) with the onset of B cell leukaemia and young knockout mice (8-12 weeks) transplanted with hepatic cancer cells. CD19⁺ Tim-1⁺ cells down-regulated the function of effector CD4⁺ CD25^low T cells ex vivo dependent on IL-10 production, and adoptive transfer of CD19⁺ Tim-1⁺ cells promoted tumour growth in mice. IL-10 production by CD19⁺ Tim-1⁺ cells was involved with the STAT3 activation. Bioinformatics analysis shows that miR-16 targets the 3'-untranslating region (3'-UTR) of STAT3 mRNA. Overexpression of miR-16 in CD19⁺ Tim-1⁺ cells inhibited STAT3 transcription and its protein expression. Thus, the loss of miR-15a/16 promoted induction of regulatory CD19⁺ Tim-1⁺ cells in tumour microenvironment. These results confirmed that miR-15a/16 could be used in tumour therapy due to its inhibition of tumour and regulatory B cells.