The immune regulation in cancer by the amino acid metabolizing enzymes ARG and IDO

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Highlights

  • •

    Arginase 1 (ARG1) and indoleamine 2,3-dioxygenase 1 (IDO1) catabolize l-arginine and l-tryptophan.

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    ARG1 and IDO1 can be activated in different myeloid cells by tumor-derived factors.

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    Enzymatic and signaling activities of ARG1 and IDO1 can induce tolerance of T lymphocytes.

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    An cross-talk among ARG1 and IDO1 can sustain a protracted tolerogenic activity in cancer environment.

  • •

    Clinical trials are designed to modulate ARG1 and IDO1 and improve cancer immunotherapy

Some enzymes degrading amino acids have evolved in mammals to dampen immune responses and maintain peripheral tolerance. The enzymes metabolizing l-arginine and l-tryptophan are particularly powerful, contributing to restrain immunity towards fetal tissues and establish neonatal tolerance. Solid tumors can hijack these formidable pathways to construct a microenvironment highly unfavorable to anti-tumor T lymphocytes able to recognize them, one of mechanisms for their immune evasion. In this review, we analyze emerging concepts in the cross-talk between cells expressing these enzymes, their immune regulatory functions and pharmacological approaches that can target them to enhance cancer immunotherapy.

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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      It was also found that arginase inhibitors enhance the level of L-arginine and therefore improve NO biosynthesis and various physiological processes regulated by NO including relaxation of smooth muscle tissues, nervous and immune systems, and sexual arousal disorder [20–22]. Moreover, arginase plays a major role in the ornithine cycle, where L-ornithine is involved in the biosynthesis of polyamines including spermine, spermidine, proline (involved in collagen, fibrin, and fibrotic tissue) and glutamate [23,24,16]. This provoked the investigation of the binding of nor-NOHA inhibitor to arginase as to why this inhibitor was reported to have distinguishing characteristics of coordination compared to other inhibitors.

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    *

    Giada Mondanelli and Stefano Ugel contributed equally to this work.

    **

    Ursula Grohmann and Vincenzo Bronte contributed equally to this work.

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