Indoleamine 2,3-dioxygenase (IDO) has immunoregulatory roles associated with tryptophan metabolism. These include counter-regulation (controlling inflammation) and acquired tolerance in T cells. ...Recent findings reveal that IDO can be triggered by innate responses during tumorigenesis, and also by attempted T cell activation, either spontaneous or due to immunotherapy. Here we review the current understanding of mechanisms by which IDO participates in the control of inflammation and in peripheral tolerance. Focusing on the tumor microenvironment, we examine the role of IDO in response to apoptotic cells and the impact of IDO on Treg cell function. We discuss how the counter-regulatory and tolerogenic functions of IDO can be targeted for cancer immunotherapy and present an overview of the current clinical progress in this area.
Cells expressing IDO suppress innate and adaptive immunity to promote tolerance by catabolizing the amino acid tryptophan (Trp) and other indole compounds. Interferon type I (IFN-I) and type II ...(IFN-II) produced at sites of inflammation or by activated immune cells are potent IDO inducers because mammalian IDO genes contain IFN response elements. Elevated IDO expression by dendritic cells (DCs) is of particular significance because IDO activity converts mature DCs into tolerogenic APCs that suppress effector T cells (Teff) and promote regulatory T cells (Tregs), thereby promoting tolerance. Local Trp depletion and production of immune suppressive Trp catabolites contribute to tolerogenic processes by activating metabolic pathways responsive to amino acid withdrawal and aryl hydrocarbon signaling, respectively. Sustained IDO elevation creates local immune privilege that protects tissues from immune-mediated damage and allows tissues to heal. This response occurs in lymphoid tissues when DNA released by dying tissue cells is sensed to induce specialized DC subsets to acquire tolerogenic phenotypes. The tolerogenic effects of IDO also promote tumorigenesis and help establish immune checkpoints in cancer, as malignant cells are protected from immune surveillance. Similar processes may attenuate host immunity to some pathogens that persist in immunocompetent individuals. However, if inflammation with IDO involvement is not resolved, chronic immune activation at such sites causes progressive tissue damage over time. Another effect of sustained IDO activity is enhanced pain sensitivity, as some Trp catabolites produced by cells expressing IDO are neuroactive. In this review, we summarize links between IDO and chronic inflammatory diseases and discuss prospects for exploiting IDO and Trp catabolism to suppress immunity and promote tolerance for clinical benefit, with particular emphasis on protecting tissues from destructive autoimmunity.
Sustained access to nutrients is a fundamental biological need, especially for proliferating cells, and controlling nutrient supply is an ancient strategy to regulate cellular responses to stimuli. ...By catabolizing the essential amino acid TRP, cells expressing the enzyme indoleamine 2,3 dioxygenase (IDO) can mediate potent local effects on innate and adaptive immune responses to inflammatory insults. Here, we discuss recent progress in elucidating how IDO activity promotes local metabolic changes that impact cellular and systemic responses to inflammatory and immunological signals. These recent developments identify potential new targets for therapy in a range of clinical settings, including cancer, chronic infections, autoimmune and allergic syndromes, and transplantation.
Indoleamine 2,3-dioxygenase (IDO) is an enzyme that degrades the essential amino acid tryptophan. The concept that cells expressing IDO can suppress T-cell responses and promote tolerance is a ...relatively new paradigm in immunology. Considerable evidence now supports this hypothesis, including studies of mammalian pregnancy, tumour resistance, chronic infections and autoimmune diseases. In this review, we summarize key recent developments and propose a unifying model for the role of IDO in tolerance induction.
Abstract
CD73, an ecto-5′-nucleotidase (NT5E), serves as an immune checkpoint by generating adenosine (ADO), which suppresses immune activation through the A
2A
receptor. Elevated CD73 levels in ...tumor tissues correlate with poor clinical outcomes. However, the crucial source of CD73 activity within the tumor microenvironment remains unspecified. Here, we demonstrate that cancer-associated fibroblasts (CAFs) constitute the prominent CD73
hi
population in human colorectal cancers (CRCs) and two CD73
−
murine tumor models, including a modified CRC. Clinically, high CAF abundancy in CRC tissues correlates strongly with elevated CD73 activity and poor prognosis. Mechanistically, CAF-CD73 expression is enhanced via an ADO-A
2B
receptor-mediated feedforward circuit triggered by tumor cell death, which enforces the CD73-checkpoint. Simultaneous inhibition of A
2A
and A
2B
pathways with CD73-neutralization synergistically enhances antitumor immunity in CAF-rich tumors. Therefore, the strategic and effective targeting of both the A
2B
-mediated ADO-CAF-CD73 feedforward circuit and A
2A
-mediated immune suppression is crucial for improving therapeutic outcomes.
Tumors arise from normal cells of the body through genetic mutation. Although such genetic mutation often leads to the expression of abnormal antigens, the immune system fails to respond effectively ...to these antigens; that is, it is tolerant of these antigens. This acquired state of tolerance must be overcome for cancer immunotherapy to succeed. Indoleamine 2,3-dioxygenase (IDO) is one molecular mechanism that contributes to tumor-induced tolerance. IDO helps create a tolerogenic milieu in the tumor and the tumor-draining lymph nodes, both by direct suppression of T cells and enhancement of local Treg-mediated immunosuppression. It can also function as an antagonist to other activators of antitumor immunity. Therefore, strategies to block IDO might enhance the effectiveness of tumor immunotherapy.
At sites of inflammation, certain regulatory T cells (Treg cells) can undergo rapid reprogramming into helper-like cells without loss of the transcription factor Foxp3. We show that reprogramming is ...controlled by downregulation of the transcription factor Eos (Ikzf4), an obligate corepressor for Foxp3. Reprogramming was restricted to a specific subset of “Eos-labile” Treg cells that was present in the thymus and identifiable by characteristic surface markers and DNA methylation. Mice made deficient in this subset became impaired in their ability to provide help for presentation of new antigens to naive T cells. Downregulation of Eos required the proinflammatory cytokine interleukin-6 (IL-6), and mice lacking IL-6 had impaired development and function of the Eos-labile subset. Conversely, the immunoregulatory enzyme IDO blocked loss of Eos and prevented the Eos-labile Treg cells from reprogramming. Thus, the Foxp3+ lineage contains a committed subset of Treg cells capable of rapid conversion into biologically important helper cells.
Display omitted
•A subset of Treg cells shows labile expression of the corepressor Eos•These Treg cells can reprogram into helper cells without losing Foxp3•Eos-labile Treg cells are constitutively present in thymus, lymph nodes, and spleen•Reprogrammed Treg cells can help support priming of effector T cells to new antigen
Cancer immunotherapy is a new and promising option for cancer treatment. Unlike traditional chemo- and radiotherapy, immunotherapy actives host immune system to attack malignancies, and this ...potentially offers long-term protection from recurrence with less toxicity in comparison to conventional chemo- and radiation therapy. In adoptive CD8+ T cell therapy (ACT), large numbers of tumor-specific T cells are sourced from patients and expanded in vitro and infused back to patients. T cells can be expanded from naturally-induced tumor-specific CD8+ T cells isolated from tumor infiltrating lymphocytes (TIL) or genetically-modified autologous circulating CD8+ T cells. The engineered T cells expressed tumor-specific antigen receptors including chimeric antigen receptors (CARs) and T cell receptors (TCRs), prepared from cultured B and T cell clones, respectively. The most successful ACT, anti-CD19 chimeric antigen receptor T (CAR-T) cell therapy directed against B cell lymphoma, is already approved for use based on evidence of efficacy. Efficacy of solid tumors is not yet forthcoming. This review summarizes current technology developments using ACT in clinical trials. In this review, differences between various ACT approaches are discussed. Furthermore, resistance factors in the tumor microenvironment are also considered, as are immune related adverse effects, critical clinic monitoring parameters and potential mitigation approaches.
•Adoptive CD8+ T cell therapy against cancer starts to achieve encouraging results.•CAR-T and TCR-T of gene-engineered T cells strengthens the CD8+T cell-based immunotherapy.•Tumor antigen mutation, tumor microenvironment, short persistence of T cells and toxicity obstruct immunotherapy.