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

- Arginase 1 (ARG1) and indoleamine 2,3-dioxygenase 1 (IDO1) catabolize l-arginine and l-tryptophan.
- ARG1 and IDO1 can be activated in different myeloid cells by tumor-derived factors.
- Enzymatic and signaling activities of ARG1 and IDO1 can induce tolerance of T lymphocytes.
- 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.