Editorial [Hot Topic: IDO1, Cancer and Cancer-Associated Inflammation (Guest Editor: Sergio Rutella)]

Indoleamine 2,3-dioxygenase 1 (IDO1) is a tryptophan-catabolizing enzyme expressed by professional antigen presenting cells such as dendritic cells (DC) or by a variety of cell types at sites of inflammation. IDO1 has been implicated in the development of immune tolerance to tumors. It is likely that IDO1 is not the only immune regulatory molecule but it is part of a more complex network of interactions and regulatory pathways that are operational in the DC compartment and possibly in other cell types. The biochemical properties of IDO1 are addressed in the first article, from Dr. Lancellotti and co-workers, which extensively covers the structural and functional properties of the enzyme, with a view to the development of novel inhibitor molecules. They also provide a thorough discussion of the ”ideal” inhibitor of IDO1, based on our current knowledge of the structural elements responsible for the optimal interaction with the catalytic site of IDO1. Dr. Fallarino and Dr. Grohmann discuss the contribution of IDO1 to the generation of regulatory T cells (Treg), a T-cell subset with remarkable plasticity that has attracted much attention over the last years. They also address the relative contribution of tryptophan starvation and kynurenine production to the amplification of Treg cells and, even more intriguingly, they focus on the inter-relations and interconversions between Treg cells and Th17, a recently described T-cell subset with pro-inflammatory actions. These data open a fascinating scenario and point to IDO1 as a molecular mechanism controlling the adaptability of Treg cells and ultimately dictating the balance between immunity and tolerance. Articles in this Issue also impart essential information on IDO1 expression and regulation in the antigen-presenting cell compartment. Dr. Heitger and Dr. Trabanelli provide us with an overview of the mechanisms that control IDO1 transcription and expression in human DC. The Authors also discuss the implications of the pharmacological manipulation of IDO1 activity in pertinent clinical scenarios such as cancer, hematopoietic stem cell transplantation and autoimmunity. Dr. Munn reviews the current evidence interconnecting the IDO pathway with Treg biology. As clearly stated in this paper, IDO is likely to represent a crucial regulatory checkpoint that controls the differentiation of naïve T cells into Treg cells, the activation of mature, preexisting Treg cells and the inflammation-induced conversion of Treg cells into pro-inflammatory T helper-like cells, a phenomenon termed “reprogramming”. These are important advances in our understanding of Treg-mediated suppression in cancer, also in view of the successful application of IDO-inhibitor drugs to the clinic. Moving to the role of IDO1 in infectious diseases, Dr. Boasso provides a close analysis of the down-stream effects of IDO over-activation on the immune alterations that characterize HIV disease. This review examines the mechanisms of IDO1 induction during HIV infection and discusses how IDO1 contributes to HIV immunopathogenesis through the inhibition of T-cell responses, the alteration of the Th1/Th2 balance, and the generation of Treg cells at sites of active viral replication. This knowledge opens exciting therapeutic perspectives aimed at inhibiting the IDO pathway in HIV-infected patients. Dr. Prendergast and co-workers present a discussion on IDO1 as a regulator of cancer-associated inflammation rather than simply a suppressor of immune function. IDO1 can also be viewed as a candidate molecule to define cancer-associated inflammation as it is distinguished from chronic inflammatory states that are not associated with cancer. The Authors offer a new perspective whereby IDO1 activity defines a state that can support, or in some cases antagonize, disease development and progression. On a related point, Dr. Cesario and co-workers discuss the inter-connections between IDO1 and cyclooxygenase (COX)-2, an enzyme involved in the biosynthesis of prostanoids. COX-2-derived prostaglandins contribute to inflammation and induce IDO1 as well as Treg activity, potentially driving cancer-associated immune suppression. Selective COX-2 inhibitors reduce IDO1 protein levels and augment the efficacy of anti-tumor DC-based vaccines, thus pointing to this class of drugs as potential modulators of IDO1 function in vivo. In conclusion, this Issue introduces the most recent findings and advances on IDO1 expression and regulation in diverse clinical settings, including chronic inflammation, HIV infection and cancer. Importantly, IDO inhibitor drugs have now entered the clinical arena and are being offered to patients with advanced cancer. This will hopefully become a viable therapeutic option also for patients with HIV infection and with certain inflammatory and autoimmune conditions.