Arginase, Nitric Oxide Synthase, and Novel Inhibitors of L-arginine Metabolism in Immune Modulation

In higher organisms, the control of amino acid metabolism has been identified as an evolutionarily preserved strategy for limiting the expansion of actively proliferating cells, including antigen-activated T lymphocytes, and tumor cells have surreptitiously adopted it to avoid or restrain attack by the immune system. Tumor growth is often associated with an altered metabolism of the amino acid L-arginine (L-Arg) by the enzymes nitric oxide synthase (NOS) and arginase (ARG). In tumor-recruited myeloid cells or in cancerous cells the consequence of their activities causes L-Arg deprivation or release of NO, which have been shown to have profound effects directly on tumor outgrowth as well as on the regulation of antitumor T-cell-mediated immune responses. Experimental findings indicate that when either one of the two enzymes is active, the net effect on T lymphocytes can be attributed to cell cycle arrest whereas the concomitant activation of both enzymes within the same environment can lead to T-cell death by apoptosis. Moreover, an increasing amount of evidence reveals an intricate system of circuits controlling either pathway or their crosstalk in cancer and in immune cells. This highlights the broad range of cellular processes that might be affected by ARG and NOS activity. In general, immune regulation by L-Arg metabolism is not antigen specific but requires that T cells are activated through their clonotypic T-cell receptor in order to be susceptible to these inhibitory circuits. In this chapter, the main processes of tumor immunity influenced by L-Arg metabolism will be discussed, along with the description of novel compounds that can deactivate these metabolic pathways in tumor-bearing hosts and thus help to restore immune reactivity against cancer.