Arginine regulation by myeloid derived suppressor cells and tolerance in cancer: mechanisms and therapeutic perspectives

Abstract

Patients with cancer have an impaired T-cell response that can decrease the potential therapeutic benefit of cancer vaccines and other forms of immunotherapy. L-arginine (L-Arg) is a conditionally essential amino acid that is fundamental for the function of T lymphocytes. Recent findings in tumor-bearing mice and cancer patients indicate that increased metabolism of L-Arg by myeloid derived suppressor cells (MDSCs) producing arginase I inhibits T-lymphocyte responses. Here we discuss some of the most recent concepts how MDSC expressing arginase I may regulate T-cell function in cancer and other chronic inflammatory diseases and suggest possible therapeutic interventions to overcome this inhibitory effect.

Fig. 1. l-Arg metabolism

l-Arginine can be metabolized by NOS into NO and citrulline. Alternatively, arginase (I and II) can convert l-Arg into urea and ornithine, with the latter being the substrate for the synthesis of polyamines need to sustain cell proliferation. For the sake of simplicity, emphasis is on enzymes that directly metabolize l-Arg. This diagram should not be interpreted to indicate that all of these enzymes are expressed simultaneously in any given cell type.

Fig. 2. Control of translation by eIF2α

Multiple signals can trigger the phosphorylation of eIF2α, including nutrient starvation (GCN2), dsRNA (PKN), unfolded proteins (PERK), and oxidative stress (HRI). Phospho-eIF2α binds to the IF2β complex, preventing its translocation and inhibiting translation.

Fig. 3. T-cell dysfunction induced by arginase I

Tumor cells expressing COX-2 and releasing PGE₂ induce the expression of arginase I and CAT-2B in MDSC. This expression leads to a reduction of extracellular levels of l-Arg, which activates GCN2 and inhibits the expression of CD3ζ, cyclin D3, and cdk4 through post-transcriptional and translational mechanisms.