Selective mRNA translation governs the tumor-associated macrophage phenotype

Tumor-associated macrophages (TAMs) continuously tune their immune modulatory properties, but how gene expression programs coordinate this is largely unknown. Selective mRNA translation facilitates reshaping of proteomes without changes in abundance of corresponding mRNAs and plays pivotal roles in regulating immune cell plasticity. Using polysome-profiling developed for small samples we show that, during tumor growth, gene expression in TAMs is predominately modulated via mRNA-selective changes in translational efficiencies targeting key cellular functions including cell proliferation and metabolism. These changes in translational efficiencies paralleled accumulation of immunosuppressive macrophages with augmented phosphorylation of eIF4E, a target of the MNK1 and MNK2 kinases, whose altered phosphorylation selectively modulates mRNA translation. Furthermore, suppression of MNK2-signaling reprogrammed immunosuppressive macrophages towards a pro-inflammatory phenotype with the ability to activate CD8+ T cells. Thus, selective changes of mRNA translation depending on MNK2-signaling represents a key node regulating macrophage immunosuppressive functions. Macrophages were sorted from tumors of different sizes and translatomes and transcriptomes were compared using polysome-profiling