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Tumor-driven immune suppression is a major barrier to successful immunotherapy in ovarian carcinomas (OvCa). Among various mechanisms responsible for immune suppression, arginase-1 (ARG1)-carrying small extracellular vesicles (EVs) emerge as important contributors to tumor growth and tumor escape from the host immune system. Here, we report that small EVs found in the ascites and plasma of OvCa patients contain ARG1. EVs suppress proliferation of CD4 + and CD8 + T-cells in vitro and in vivo in OvCa mouse models. In mice, ARG1-containing EVs are transported to draining lymph nodes, taken up by dendritic cells and inhibit antigen-specific T-cell proliferation. Increased expression of ARG1 in mouse OvCa cells is associated with accelerated tumor progression that can be blocked by an arginase inhibitor. Altogether, our studies show that tumor cells use EVs as vehicles to carry over long distances and deliver to immune cells a metabolic checkpoint molecule – ARG1, mitigating anti-tumor immune responses. Cancer cells employ a variety of ways to escape the immune system. Here, the authors show that ovarian cancer cells produce small extracellular vescicles containing arginase 1 that are taken up by dendritic cells in the draining lymph nodes, resulting in inhibition of antigen-specific T-cell proliferation.

A growing body of evidence indicates that, over the course of evolution of the immune system, arginine has been selected as a node for the regulation of immune responses. An appropriate supply of arginine has long been associated with the improvement of immune responses. In addition to being a building block for protein synthesis, arginine serves as a substrate for distinct metabolic pathways that profoundly affect immune cell biology; especially macrophage, dendritic cell and T cell immunobiology. Arginine availability, synthesis, and catabolism are highly interrelated aspects of immune responses and their fine-tuning can dictate divergent pro-inflammatory or anti-inflammatory immune outcomes. Here, we review the organismal pathways of arginine metabolism in humans and rodents, as essential modulators of the availability of this semi-essential amino acid for immune cells. We subsequently review well-established and novel findings on the functional impact of arginine biosynthetic and catabolic pathways on the main immune cell lineages. Finally, as arginine has emerged as a molecule impacting on a plethora of immune functions, we integrate key notions on how the disruption or perversion of arginine metabolism is implicated in pathologies ranging from infectious diseases to autoimmunity and cancer.

Arginase activity and arginine metabolism in immune cells have important consequences for health and disease. Their dysregulation is commonly observed in cancer, autoimmune disorders and infectious diseases. Following the initial description of a role for arginase in the dysfunction of T cells mounting an antitumour response, numerous studies have broadened our understanding of the regulation and expression of arginases and their integration with other metabolic pathways. Here, we highlight the differences in arginase compartmentalization and storage between humans and rodents that should be taken into consideration when assessing the effects of arginase activity. We detail the roles of arginases, arginine and its metabolites in immune cells and their effects in the context of cancer, autoimmunity and infectious disease. Finally, we explore potential therapeutic strategies targeting arginases and arginine. This Review provides an overview of arginine and arginase function in immune cells, at the steady state and during disease. It considers the relevance of this pathway for metabolic, immune and genetic regulation, together with possible therapeutic interventions.

Amino acid metabolism is a critical regulator of the immune response, and its modulating becomes a promising approach in various forms of immunotherapy. Insufficient concentrations of essential amino acids restrict T-cells activation and proliferation. However, only arginases, that degrade L-arginine, as well as enzymes that hydrolyze L-tryptophan are substantially increased in cancer. Two arginase isoforms, ARG1 and ARG2, have been found to be present in tumors and their increased activity usually correlates with more advanced disease and worse clinical prognosis. Nearly all types of myeloid cells were reported to produce arginases and the increased numbers of various populations of myeloid-derived suppressor cells and macrophages correlate with inferior clinical outcomes of cancer patients. Here, we describe the role of arginases produced by myeloid cells in regulating various populations of immune cells, discuss molecular mechanisms of immunoregulatory processes involving L-arginine metabolism and outline therapeutic approaches to mitigate the negative effects of arginases on antitumor immune response. Development of potent arginase inhibitors, with improved pharmacokinetic properties, may lead to the elaboration of novel therapeutic strategies based on targeting immunoregulatory pathways controlled by L-arginine degradation.

An extensive fibroinflammatory stroma rich in macrophages is a hallmark of pancreatic cancer. In this disease, it is well appreciated that macrophages are immunosuppressive and contribute to the poor response to immunotherapy; however, the mechanisms of immune suppression are complex and not fully understood. Immunosuppressive macrophages are classically defined by the expression of the enzyme Arginase 1 (ARG1), which we demonstrated is potently expressed in pancreatic tumor-associated macrophages from both human patients and mouse models. While routinely used as a polarization marker, ARG1 also catabolizes arginine, an amino acid required for T cell activation and proliferation. To investigate this metabolic function, we used a genetic and a pharmacologic approach to target Arg1 in pancreatic cancer. Genetic inactivation of Arg1 in macrophages, using a dual recombinase genetically engineered mouse model of pancreatic cancer, delayed formation of invasive disease, while increasing CD8 + T cell infiltration. Additionally, Arg1 deletion induced compensatory mechanisms, including Arg1 overexpression in epithelial cells, namely Tuft cells, and Arg2 overexpression in a subset of macrophages. To overcome these compensatory mechanisms, we used a pharmacological approach to inhibit arginase. Treatment of established tumors with the arginase inhibitor CB-1158 exhibited further increased CD8 + T cell infiltration, beyond that seen with the macrophage-specific knockout, and sensitized the tumors to anti-PD1 immune checkpoint blockade. Our data demonstrate that Arg1 drives immune suppression in pancreatic cancer by depleting arginine and inhibiting T cell activation.

This study used in vitro experiments and an orthotopic glioblastoma (GBM) mouse model to test the efficacy of human pegylated arginase I formulation, BCT-100, against the incurable cancer, GBM. Arginine auxotrophy in GBM was verified in silico and in vitro by absence of OTC and ASS1 expression. BCT-100 inhibited growth and induced cell death in four GBM cell lines in vitro. Transcriptomics of U87 and U373 treated with BCT-100 responded differently. BCT-100-treated U87 showed autophagy induction. Cytotoxicity enhancement was observed in four cell lines treated with BCT-100 + chloroquine (CQ). CQ + BCT-100 induced caspase-dependent and caspase-independent cell death in luciferase-transfected U87 (U87(lf+)). BCT-100 or CQ monotherapy, but not BCT-100+ CQ, prolonged survival of intracranial U87(lf+)-bearing mice similarly without suppressing tumor growth. Mouse microglia cell BV2 protected U87(lf+) from BCT100-induced cytotoxicity in transwell co-culture. Etoposide suppressed BV2’s protection to U87(lf+) upon BCT-100 treatment by suppressing the growth and inducing cell death of BV2, suggesting microglial suppression as a strategy for enhancing the efficacy of BCT-100. Microglial protection may explain the in vitro and in vivo discrepancies. Further investigation into microglia/GBM interactions may help improve the efficacy of arginine deprivation therapy against GBM.

Exosomes, abundant in blood, deliver various molecules to recipient cells. Endothelial cells are directly exposed to circulating substances. However, how endothelial cells respond to serum exosomes (SExos) and the implications in diabetes-associated vasculopathy have never been explored. In the present study, we showed that SExos from diabetic db/db mice (db/db SExos) were taken up by aortic endothelial cells, which severely impaired endothelial function in nondiabetic db/m⁺ mice. The exosomal proteins, rather than RNAs, mostly account for db/db SExos-induced endothelial dysfunction. Comparative proteomics analysis showed significant increase of arginase 1 in db/db SExos. Silence or overexpression of arginase 1 confirmed its essential role in db/db SExos-induced endothelial dysfunction. This study is a demonstration that SExos deliver arginase 1 protein to endothelial cells, representing a cellular mechanism during development of diabetic endothelial dysfunction. The results expand the scope of bloodborne substances that monitor vascular homeostasis.

The cell-intrinsic pathways controlling the function of innate lymphoid cells are poorly defined. Artis and colleagues demonstrate that ILC2s selectively express arginase 1 and that this is critical for their bioenergetics, proliferation and function. Group 2 innate lymphoid cells (ILC2s) regulate tissue inflammation and repair after activation by cell-extrinsic factors such as host-derived cytokines. However, the cell-intrinsic metabolic pathways that control ILC2 function are undefined. Here we demonstrate that expression of the enzyme arginase-1 (Arg1) during acute or chronic lung inflammation is a conserved trait of mouse and human ILC2s. Deletion of mouse ILC-intrinsic Arg1 abrogated type 2 lung inflammation by restraining ILC2 proliferation and dampening cytokine production. Mechanistically, inhibition of Arg1 enzymatic activity disrupted multiple components of ILC2 metabolic programming by altering arginine catabolism, impairing polyamine biosynthesis and reducing aerobic glycolysis. These data identify Arg1 as a key regulator of ILC2 bioenergetics that controls proliferative capacity and proinflammatory functions promoting type 2 inflammation.

Molecular diversity of microglia, the resident immune cells in the CNS, is reported. Whether microglial subsets characterized by the expression of specific proteins constitute subtypes with distinct functions has not been fully elucidated. Here we describe a microglial subtype expressing the enzyme arginase-1 (ARG1; that is, ARG1 + microglia) that is found predominantly in the basal forebrain and ventral striatum during early postnatal mouse development. ARG1 + microglia are enriched in phagocytic inclusions and exhibit a distinct molecular signature, including upregulation of genes such as Apoe , Clec7a , Igf1 , Lgals3 and Mgl2 , compared to ARG1 – microglia. Microglial-specific knockdown of Arg1 results in deficient cholinergic innervation and impaired dendritic spine maturation in the hippocampus where cholinergic neurons project, which in turn results in impaired long-term potentiation and cognitive behavioral deficiencies in female mice. Our results expand on microglia diversity and provide insights into microglia subtype-specific functions. The molecular diversity of microglia has been described. Here the authors show that ARG1-expressing microglia are enriched in phagocytic inclusions and are involved in hippocampal innervation and spine maturation in mice. ARG1-expressing microglia also modulate cognition in a sex-dependent manner.

Autophagy captures intracellular components and delivers them to lysosomes, where they are degraded and recycled to sustain metabolism and to enable survival during starvation 1 – 5 . Acute, whole-body deletion of the essential autophagy gene Atg7 in adult mice causes a systemic metabolic defect that manifests as starvation intolerance and gradual loss of white adipose tissue, liver glycogen and muscle mass 1 . Cancer cells also benefit from autophagy. Deletion of essential autophagy genes impairs the metabolism, proliferation, survival and malignancy of spontaneous tumours in models of autochthonous cancer 6 , 7 . Acute, systemic deletion of Atg7 or acute, systemic expression of a dominant-negative ATG4b in mice induces greater regression of KRAS-driven cancers than does tumour-specific autophagy deletion, which suggests that host autophagy promotes tumour growth 1 , 8 . Here we show that host-specific deletion of Atg7 impairs the growth of multiple allografted tumours, although not all tumour lines were sensitive to host autophagy status. Loss of autophagy in the host was associated with a reduction in circulating arginine, and the sensitive tumour cell lines were arginine auxotrophs owing to the lack of expression of the enzyme argininosuccinate synthase 1. Serum proteomic analysis identified the arginine-degrading enzyme arginase I (ARG1) in the circulation of Atg7 -deficient hosts, and in vivo arginine metabolic tracing demonstrated that serum arginine was degraded to ornithine. ARG1 is predominantly expressed in the liver and can be released from hepatocytes into the circulation. Liver-specific deletion of Atg7 produced circulating ARG1, and reduced both serum arginine and tumour growth. Deletion of Atg5 in the host similarly regulated circulating arginine and suppressed tumorigenesis, which demonstrates that this phenotype is specific to autophagy function rather than to deletion of Atg7 . Dietary supplementation of Atg7 -deficient hosts with arginine partially restored levels of circulating arginine and tumour growth. Thus, defective autophagy in the host leads to the release of ARG1 from the liver and the degradation of circulating arginine, which is essential for tumour growth; this identifies a metabolic vulnerability of cancer. Mice with whole-body or liver-specific deletion of Atg7 release circulating arginase I and have reduced levels of serum arginine, which impairs the growth of allografted arginine-auxotrophic tumours.