Metabolic Reprogramming of Arginine in Tumor Stem Cells Facilitates Immune Escape

Abstract

Abstract While numerous studies have focused on metabolic reprogramming that leads to immunosuppression in the primary tumor microenvironment, it is not known whether metabolic reprogramming of metastatic tumor cells contributes to immune escape during travel in an exposed environment where they are subject to immune attack. Tumor stem cells (TSCs) are best known for their contributions to tumor metastasis. Using two models of breast cancer (mouse 4T1 and human BT474), we have determined increased arginine metabolism when TSCs encounter inactive or CD3/CD28 activated effector T cells. This manifests as increased expression of the cationic amino acid transporter 2, SLC7A2. However, other changes in arginine metabolism only occur in TSCs encountering activated T cells, including increased expression/activities of inducible nitric oxide synthase (NOS2), protein arginine deiminase and arginine decarboxylase, and a slightly increased expression/activity of Arginase. Using fluorescent Dansyl-Arginine, we have demonstrated competition between TSCs and T cells for Arginine uptake. Thus, the TSC limits activation and expansion of T cells encountered. Interestingly, a reprogramming of enzymes that favor arginine methylation (increased arginine methyltransferases and decreased arginine demethylase) occurs. As a consequence, there is an increase in secreted asymmetric dimethylarginine (ADMA). Here, we report that giving ADMA to human monocytes leads to polarization of macrophages to the M2 phenotype. In summary, our results show a novel metabolic effect in TSCs by reprogramming arginine uptake, metabolism and modification, which in turn modifies functions in approaching immune cells leading to successful immune escape.