The immune regulation in cancer by the amino acid metabolizing enzymes ARG and IDO
Introduction
Cancer immunotherapy has profoundly changed the outcome of cancer patients. However, recent evidence indicates that immunotherapy, including novel antibodies blocking T cell checkpoints, is successful in a proportion of patients. For example, the efficacy of Nivolumab, an anti-PD1 monoclonal antibody that has been approved by the Food and Drug Administration (FDA) for the treatment of patients with advanced non-small cell lung cancer, is far from optimal with a response rate of 15–20% [1]. Therefore, there is an urgent need to identify and remove tumor microenvironment cues that limit T cell functionality. One emerging strategy, which is being tested in clinical trials (Table 1, Table 2, Table 3), is based on the pharmacological modulation of enzymes that degrade amino acids.
Section snippets
Arginase in the tumor microenvironment
l-arginine is a non-essential amino acid that is involved in the synthesis of many metabolites, such as nitric oxide (NO) and polyamines (putrescine, spermidine, spermine), as well as in protein post-translational modification and immune regulation [2]. Therefore, l-arginine availability can intervene in different aspects of reprogramming energy metabolism, recently identified as a new hallmark of cancer [3]. High levels of intracellular l-arginine not only favor the T cell fitness, activation,
IDO1: not just catabolism of tryptophan
An important mechanism of immune resistance in tumors involves the metabolism of l-tryptophan (Trp), the rarest essential amino acid found in food. More than 90% of Trp entered with diet is catabolized via the kynurenine pathway, a cascade of enzymatic steps that produces several biologically active molecules, collectively known as kynurenines, before finally producing the essential pyridine nucleotide, NAD+ (nicotinamide adenine dinucleotide) [2, 31, 32, 33]. NAD+ is a fundamental coenzyme for
TGF-β, Arg1, and IDO1: an immunosuppressive triad at work in dendritic cells
As a whole, data available on IDO1 and ARG1 suggest that the two enzymes work in different cells, either through pathways that deplete the amino acids or via the combined effects of immunoregulatory metabolites and signaling activity. While IL-4 and IFN-γ are the main inducers of ARG1 [24] and IDO1 [31] in myeloid cells, respectively, the cytokine TGF-β can affect both enzymes, although apparently in different cell types. TGF-β is indeed able to confer both IDO1 competence and tolerogenic
Pharmacological control
The anti-tumor effect of ARG inhibitors is suggested by in vitro and in vivo preclinical data: NG-hydroxy-l-arginine [NOHA] inhibits ARG activity restores tumor-infiltrating T lymphocyte responsiveness to stimulation in human prostate carcinoma organ cultures [19]; Nω-hydroxy-nor-Arginine [nor-NOHA] abrogates T cell proliferative arrest, favoring the immune attack of cancer cells [53]; analogously, the S-(2-Boronoethyl)-l-cysteine hydrochloride [BEC hydrochloride] administration in association
Conflict of interest
None.
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgments
This work was supported by the European Research Council (338954; to UG) and grants from the Italian Association of Cancer Research (12182 and 14103; to VB).
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Giada Mondanelli and Stefano Ugel contributed equally to this work.
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Ursula Grohmann and Vincenzo Bronte contributed equally to this work.