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

Abstract

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+CD25low 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.