Tumor-Derived Exosomes Drive Immunosuppressive Macrophages in a Pre-Metastatic Niche Through NF-Kb Dependent Glycolytic Metabolic Reprogramming

The formation of a pre-metastatic niche is a fundamental requirement for primary tumor metastasis. One of the defining characteristics of a pre-metastatic niche is infiltration of immunosuppressive macrophages. However, how these macrophages acquire their immunosuppressive phenotype remains largely unexplored. Here, we demonstrate that tumor-derived exosomes (TDE) polarize macrophages towards an immunosuppressive phenotype characterized by increased PD-L1 expression through NF-kB-dependent metabolic reprogramming in mice and humans. While NF-κB has previously been shown to act as a direct transcription factor for PD-L1, we report a novel mechanism where TDE-induced NF-κB activation drives PD-L1 expression by augmenting the glycolytic capacity of macrophages through two separate pathways. First, NF-κB increases glucose uptake into macrophages via a HIF-1α/GLUT-1-dependent mechanism. Secondly, elevated NOS2-dependent nitric oxide inhibits mitochondrial oxidative phosphorylation resulting in an increased conversion of pyruvate to lactate. Lactate then feeds back on NF-κB further increasing PD-L1 expression. Analysis of metastasis negative draining lymph nodes of non-small cell lung cancer patients revealed that macrophage PD-L1 expression positively correlates with expression levels of GLUT-1 and exosomal release genes YKT6 and TSG101 from primary tumors. Collectively, our study provides a novel mechanism by which macrophages within a pre-metastatic niche acquire their immunosuppressive phenotype and identifies an important link between exosomes, metabolism, and metastasis.