Cancer Therapy Vol 4, page 27 Cancer Therapy Vol 4, 27-34, 2006
The role of IDO in immune system evasion of malignancy: Another piece to the tolerance puzzle Review Article
Jeannine A. Villella, Kunle Odunsi, Shashikant Lele* Roswell Park Cancer Institute, Department of Surgery, Division of Gynecologic Oncology
__________________________________________________________________________________ *Correspondence: Shashikant B. Lele, MD, Chair, Gynecologic Oncology, Department of Surgery, Roswell Park Cancer Institute, School of Medicine & Biomedical Sciences, University at Buffalo, Elm & Carlton Streets, Buffalo, NY 14209, USA; e-mail: Shashikant.Lele@RoswellPark.org Key words: Immune Response, immune tolerance, indolamine 2, 3 dioxygenase Abbreviations: Indoleamine 2, 3-dioxygenase, (IDO); Lewis lung carcinoma, (LLC); lipopolysaccharide, (LPS); major histocompatibility complex, (MHC); tumor draining lymph nodes, (TDLN); tumor necrosis factor, (TNF) Received: 10 October 2005; Accepted: 25 October 2005; electronically published: January 2006
Summary Mechanisms of immune system evasion have tremendous implications in health and disease including inflammation, autoimmune disease, organ transplantation, pregnancy and carcinogenesis. The immune system discriminates based on stimuli that either provokes immune response or prevents response, resulting in immune tolerance. A delicate balance is essential for normal immune function and homeostasis. Factors involved in this process are complex, and the players somewhat elusive, making the pathophysiology of immune surveillance so intriguing. Breakdown of this fundamental homeostasis can tip the scale allowing disease to prevail. This article describes one piece to the puzzle: the role of the enzyme indolamine 2, 3- dioxygenase in the anti-tumor immune response. protects us from tumor development, but also sculpts the tumor phenotype (Dunn et al, 2004). The final phase of cancer immunoediting is immune escape from the forces of immunologic control, and supports the notion that tumor cell-specific neo-antigens could cause regression of developing cancers (Burnet, 1957; 1964). This concept of immune tolerance emerged and was described as a state of specific unresponsiveness that is antigen specific. There is an overall lack of attack on self antigens that is a normal part of the immune response. Since failure of self-tolerance leads to autoimmune disease, a delicate balance is imperative for normal immune function. It is to be expected that no single mechanism can completely explain the discrimination of the immune system and regulation of immune surveillance in circumstances such as pregnancy, auto immune disease, carcinogenesis and cancer progression. One aspect of the immunoregulatory process that has gained much attention in tumor immunology over the last several years is the role of the enzyme indolamine 2, 3- dioxygenase in modulating T cell responses through the essential amino acid catabolism of tryptophan. In this review article, we will discuss the mechanism and consequence of tryptophan metabolism in T-cell-mediated immune response, and the effect it has on cancer initiation and progression. We have
I. Introduction The immune system protects from pathogens that have the potential to be lethal. In the case of tumors, they usually grow despite an intact immune system; seemingly with apparent disregard for immune system control. It is intuitive to think that the immune system would recognize tumor cells as foreign and destroy them. Unfortunately this is not always the case. In 1909, Paul Ehrlich proposed the cancer immunosurveillance hypothesis and predicted that the immune system repressed the growth of cancers that would otherwise occur with greater frequency (Ehrlich, 1909). This hypothesis was embraced by tumor immunologists until the 1970s when Stutman showed no increased frequency of cancers in nude mice (Stutman, 1974). For many decades thereafter, immunologists focused on immunologic roles in organ transplantation and pregnancy (Thomas, 1959). Nobel Prize winners F. Macfarlane Burnet and Peter Brian Metawar focused on immunologic tolerance and its role in allograft rejection, and ultimately resurrected the concept of natural immune defense against cancer. Recently, there has been a resurgence in the concept of cancer immunosurveillance, and it is more appropriately named “cancer immunoediting� (Dunn et al, 2004). Cancer immunoediting holds that the immune system not only
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