Indoleamine 2,3-dioxygenase, tumor-induced tolerance and counter-regulation
Introduction
The tryptophan-degrading enzyme indoleamine 2,3-dioxygenase (IDO) can be a potent mechanism of immunosuppression and tolerance induction in certain settings. In vitro and in vivo studies of IDO and its general role in the immune system have been recently reviewed [1]. The specific focus of the current discussion is the ways in which IDO functions in the context of tumor immunology. I will consider IDO in two potential roles: first, as a primary molecular target for cancer immunotherapy; and second, as an endogenous counter-regulatory mechanism that can secondarily antagonize the effectiveness of other immunotherapy strategies.
Section snippets
IDO and tolerance
The biological role of IDO in the immune system is still a subject of active investigation. Endogenous IDO has been implicated as one mechanism that helps maintain maternal tolerance toward the fetus [2]. This may be conceptually relevant to tumor immunology, as the fetus constitutes a large set of new antigens to which the immune system acquires tolerance [3]. IDO also regulates the severity of a variety of experimental autoimmune disorders [4, 5, 6, 7]. IDO does not, however, appear to be
Tumors exploit natural tolerogenic mechanisms
It seems unlikely that tumors would independently evolve completely novel molecular mechanisms to evade the immune system. Rather, just as the tumor co-opts preexisting host mechanisms to grow new blood vessels and perform other complex tasks, it is likely that the tumor subverts natural host mechanisms (such as IDO) to create tolerance to itself. In considering where these mechanisms might operate, it is helpful to distinguish between regulation of the afferent (priming) arm of the immune
Stochastic activation of the IDO system in tumor-bearing hosts
The two roles for IDO described above — inhibition of afferent and efferent immune responses — are not mutually exclusive, and both could operate in a given tumor. The tumor's ability to elicit IDO-mediated immune suppression (or not) presumably reflects a stochastic process of acquired mutations, driven by selection pressure from the host immune system. In this regard, it is interesting to note recent results from Muller and colleagues [24••], using a spontaneous mouse breast-tumor model (the
Use of IDO inhibitor drugs in combination therapy regimens
Although IDO may be involved in tolerance and immunosuppression in tumor-bearing hosts, it is certainly not the only mechanism participating in these processes. In the case of tolerance in particular, when the tolerant state has been acquired the role of IDO may be over (i.e. the ongoing condition of tolerance can be maintained by other mechanisms). Thus, in the setting of an established tumor, simply inhibiting IDO is not likely to be sufficient, by itself, to break tolerance. From a practical
IDO as a counter-regulatory mechanism
The preceding discussion has focused on IDO expression related to the tumor: either IDO expressed by tumor cells themselves, or IDO expressed by host cells in response to the tumor. However, there is an additional role in which IDO may be relevant to the clinical immunotherapy of cancer, and that is as an inflammation-induced counter-regulatory mechanism.
Counter-regulatory responses are important in the immune system: they help to limit the intensity and extent of strong immune responses, which
Conclusions
Much remains to be learned about the biology of IDO in general, and its role in tumor immunology in particular. The fact that IDO is frequently expressed in tumors and TDLNs, combined with its potent immunosuppressive activity in certain settings, certainly warrants further investigation. Clinically, it is encouraging that there are orally bioavailable small-molecule inhibitor drugs available to target this pathway. Finally, the fact that IDO appears to be secondarily induced by several other
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
References (47)
- et al.
Inhibition of indoleamine 2,3-dioxygenase augments trinitrobenzene sulfonic acid colitis in mice
Gastroenterology
(2003) - et al.
Specific induction of indoleamine 2,3-dioxygenase by bacterial lipopolysaccharide in the mouse lung
Arch Biochem Biophys
(1981) - et al.
Cutting Edge: Induced indoleamine 2,3 dioxygenase expression in dendritic cell subsets suppresses T cell clonal expansion
J Immunol
(2003) - et al.
Quantitative analysis of melanoma-induced cytokine-mediated immunosuppression in melanoma sentinel nodes
Clin Cancer Res
(2005) - et al.
Inhibition of tumor cell growth by interferon-γ is mediated by two distinct mechanisms dependent upon oxygen tension: induction of tryptophan degradation and depletion of intracellular nicotinamide adenine dinucleotide
J Clin Invest
(1989) - et al.
Inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1, potentiates cancer chemotherapy
Nat Med
(2005) - et al.
Proteomic analysis of cytokine induced proteins in human intestinal epithelial cells: implications for inflammatory bowel diseases
Proteomics
(2002) - et al.
Rapid and strong human CD8+ T cell responses to vaccination with peptide, IFA, and CpG oligodeoxynucleotide 7909
J Clin Invest
(2005) - et al.
Monocyte-mediated T-cell suppression and augmented monocyte tryptophan catabolism after human hematopoietic stem-cell transplantation
Blood
(2005) - et al.
Modulation of human dendritic-cell function following transduction with viral vectors: implications for gene therapy
Blood
(2005)
Expression of indoleamine 2,3-dioxygenase in dermal fibroblasts functions as a local immunosuppressive factor
J Invest Dermatol
IDO expression by dendritic cells: Tolerance and tryptophan catabolism
Nat Rev Immunol
Prevention of allogeneic fetal rejection by tryptophan catabolism
Science
Immunology at the maternal-fetal interface: lessons for T cell tolerance and suppression
Annu Rev Immunol
A defect in tryptophan catabolism impairs tolerance in nonobese diabetic mice
J Exp Med
Inhibition of experimental asthma by indoleamine 2,3-dioxygenase
J Clin Invest
Indolamine 2,3-dioxygenase is expressed in the CNS and down-regulates autoimmune inflammation
FASEB J
Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase
Nat Med
CDllc+ cells modulate pulmonary immune responses by production of indoleamine 2,3-dioxygenase
Am J Respir Cell Mol Biol
Expression of indoleamine 2,3-dioxygenase by plasmacytoid dendritic cells in tumor-draining lymph nodes
J Clin Invest
GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase
Immunity
Specific subsets of murine dendritic cells acquire potent T cell regulatory functions following CTLA4-mediated induction of indoleamine 2,3 dioxygenase
Int Immunol
A minor population of splenic dendritic cells expressing CD19 mediates IDO-dependent T cell suppression via type 1 interferon-signaling following B7 ligation
Int Immunol
Cited by (156)
Genetic Variations of Ionotropic Glutamate Receptor Pathways on Interferon-α-induced Depression in Patients with Hepatitis C Viral Infection
2021, Brain, Behavior, and ImmunityIncreased Indoleamine 2, 3-Dioxygenase expression modulates Th1/Th17/Th22 and Treg pathway in humans with Helicobacter Pylori-Infected gastric mucosa
2021, Human ImmunologyCitation Excerpt :Also, IDO is widely expressed in various cells such as epithelial cells, endothelial cells, macrophages, dendritic cells (DC), and tumor cells [2–4]. IDO expression is known to be induced by various stimuli including pathogen-associated molecular patterns (PAMP), co-stimulatory molecules, and inflammatory cytokines such as interferon gamma (INF-γ) [2]. The biologic function of the IDO enzyme is to be contributed to the control of inflammation and takes part in creation of acquired peripheral tolerance [5].
Gene expression of indoleamine and tryptophan dioxygenases and three long non-coding RNAs in breast cancer
2020, Experimental and Molecular PathologyCancer Metabolism Drives a Stromal Regenerative Response
2019, Cell Metabolism