The Metabolomics of Nitric Oxide and Reactive Nitrogen Species in Immune Editing Tumor Milieu: Influence of Nitric Oxide-Modulating Therapies

Abstract

Nitric oxide (NO), reactive nitrogen and oxygen species, hypoxia, L-arginine metabolites and peroxynitrite are contributing agents during various stages of carcinogenesis. Among these, NO contributes to various functions in the tumor microenvironment such as augmenting immune suppression, maintaining anergy to tumor associated antigens, stimulating angiogenesis, enhancing tumor growth and invasiveness, and modulating autophagy. Most cells in the tumor milieu either release NO and/or have altered physiological functions due to the influence of NO. Cancer cells evolve into a metabolic state to tolerate and reduce reactive nitrogen and oxygen species to elude oxidative damage. These cancer cells in the tumor microenvironment inhibit cellular infiltration of effector immune cells into the cancer milieu. Increased levels of CCAAT-enhancer-binding proteins such as C/EBP α and β are required for inducible Nitric Oxide Synthase (iNOS) gene expression and other transcripts for sustaining an immunosuppressive environment in growing tumors. The immunoediting property of reactive nitrogen and oxygen-modified metabolites change the functions of: intratumoral chemokines, T cell receptors, antigen specific tumor infiltrating lymphocytes (TILs), cytotoxic T lymphocyte, myeloid derived suppressive cells (MDSCs), gene expression, tumor suppressor genes, and Interferon responses which together countersignal tumor immunity. Recent studies show that reactive nitrogen species that promote tumor-mediated immune evasion can be reversed by gene therapy, immunotherapy, and chemotherapy by targeting or co-targeting excessive nitric oxide accumulation.