microRNA expression in macrophages regulates antibody-dependent effector function and B cell lymphoma therapy.

CD163 positive tumour associated macrophages (TAMs) are associated with poor response to immunochemotherapy in patients with diffuse large B cell lymphoma and comprise a significant proportion of the tumour microenvironment. Targeting these TAMs to reverse immunosuppression is an attractive approach for improving treatment response rates. A change in microRNA expression has the potential to modify hundreds of genes by interacting with multiple messenger RNA targets, thereby altering the wider cellular transcriptional profile. The manipulation of microRNAs that control macrophage behaviour may switch the global transcriptomic profiles of immunosuppressive macrophages to more activated, anti-tumour states resulting in the reversal of immune resistance and enhancement of monoclonal antibody (mAb) therapy. Our studies show a significant upregulation of microRNA 142-5p in immunosuppressive macrophages stimulated with IL4/IL13 compared to LPS/IFNγ stimulated macrophages and non-polarised controls. This upregulation of microRNA 142-5p in macrophages stimulated with immunoinhibitory cytokines IL10 and TGFbeta was also demonstrated. Inhibition of microRNA 142-5p expression in IL4/IL13 stimulated macrophages led to a significant increase in FcγRIIIA, CD40 and CD47 expression with enhanced phagocytosis of CLL cells opsonised with Rituximab when compared with non-transfected controls. Expression of microRNA 142-5p in diagnostic DLBCL patient samples was assessed using miRScope assays. These were combined with immunohistochemistry staining of CD206 to identify immunosuppressive macrophages. Combination of high microRNA 142-5p and CD206 expression correlated with a reduction in progression free survival following standard Rituximab containing chemotherapy regimens in 38 patients. Together these studies indicate the potential of targeting microRNA to repolarise macrophages and improve treatment success.