Immunosuppressive IDO in Cancer: Mechanisms of Action, Animal Models, and Targeting Strategies

Zhai, Lijie; Bell, April; Ladomersky, Erik; Lauing, Kristen L.; Bollu, Lakshmi Reddy; Sosman, Jeffrey A.; Zhang, Bin; Wu, Jennifer D.; Miller, Stephen D.; Meeks, Joshua J.; Lukas, Rimas V.; Wyatt, Eugene; Doglio, Lynn; Schiltz, Gary E.; McCusker, Robert H.; Wainwright, Derek A.

doi:10.3389/fimmu.2020.01185

Cited by 158 publications

(128 citation statements)

References 119 publications

(137 reference statements)

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“…Accordingly, the WT-mediated impairment of NK cytolytic activity was not prevented in presence of compound targeting IDO and PGE. The IDO catabolite Kynurenine and PGE are two soluble immuno-suppressive factors frequently released by tumor cells [ 42 , 43 ] ( Figure S1B ).…”

Section: Resultsmentioning

confidence: 99%

Wilms’ Tumor Primary Cells Display Potent Immunoregulatory Properties on NK Cells and Macrophages

Fiore

Vacca

Tumino

et al. 2021

Cancers

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The immune response plays a crucial defensive role in cancer growth and metastasis and is a promising target in different tumors. The role of the immune system in Wilm’s Tumor (WT), a common pediatric renal malignancy, is still to be explored. The characterization of the immune environment in WT could allow the identification of new therapeutic strategies for targeting possible inhibitory mechanisms and/or lowering toxicity of the current treatments. In this study, we stabilized four WT primary cultures expressing either a blastematous (CD56+/CD133−) or an epithelial (CD56−/CD133+) phenotype and investigated their interactions with innate immune cells, namely NK cells and monocytes. We show that cytokine-activated NK cells efficiently kill WT cells. However, after co-culture with WT primary cells, NK cells displayed an impaired cytotoxic activity, decreased production of IFNγ and expression of CD107a, DNAM-1 and NKp30. Analysis of the effects of the interaction between WT cells and monocytes revealed their polarization towards alternatively activated macrophages (M2) that, in turn, further impaired NK cell functions. In conclusion, we show that both WT blastematous and epithelial components may contribute directly and indirectly to a tumor immunosuppressive microenvironment that is likely to play a role in tumor progression.

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Section: Resultsmentioning

confidence: 99%

Wilms’ Tumor Primary Cells Display Potent Immunoregulatory Properties on NK Cells and Macrophages

Fiore

Vacca

Tumino

et al. 2021

Cancers

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“…NAD+ is important in mitochondrial bioenergetics and supplementation has been associated with increased longevity [88]. Inhibition of the first step in this pathway by inhibiting indoleamine 2,3-dioxygenase (IDO) is already an experimental strategy that has been used for treating certain types of cancer [89]. Thus, modulation of the tryptophan catabolic pathway has the potential to benefit not only musculoskeletal aging but also other age-related diseases, such as neurodegenerative disorders, cancer, and vascular diseases.…”

Section: Discussionmentioning

confidence: 99%

The Role of Tryptophan Metabolites in Musculoskeletal Stem Cell Aging

Anaya

Bollag

Hamrick

et al. 2020

IJMS

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Although aging is considered a normal process, there are cellular and molecular changes that occur with aging that may be detrimental to health. Osteoporosis is one of the most common age-related degenerative diseases, and its progression correlates with aging and decreased capacity for stem cell differentiation and proliferation in both men and women. Tryptophan metabolism through the kynurenine pathway appears to be a key factor in promoting bone-aging phenotypes, promoting bone breakdown and interfering with stem cell function and osteogenesis; however, little data is available on the impact of tryptophan metabolites downstream of kynurenine. Here we review available data on the impact of these tryptophan breakdown products on the body in general and, when available, the existing evidence of their impact on bone. A number of tryptophan metabolites (e.g., 3-hydroxykynurenine (3HKYN), kynurenic acid (KYNA) and anthranilic acid (AA)) have a detrimental effect on bone, decreasing bone mineral density (BMD) and increasing fracture risk. Other metabolites (e.g., 3-hydroxyAA, xanthurenic acid (XA), picolinic acid (PIA), quinolinic acid (QA), and NAD+) promote an increase in bone mineral density and are associated with lower fracture risk. Furthermore, the effects of other tryptophan breakdown products (e.g., serotonin) are complex, with either anabolic or catabolic actions on bone depending on their source. The mechanisms involved in the cellular actions of these tryptophan metabolites on bone are not yet fully known and will require further research as they are potential therapeutic targets. The current review is meant as a brief overview of existing English language literature on tryptophan and its metabolites and their effects on stem cells and musculoskeletal systems. The search terms used for a Medline database search were: kynurenine, mesenchymal stem cells, bone loss, tryptophan metabolism, aging, and oxidative stress.

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“…Catabolism of the essential amino acid tryptophan (Trp) by indoleamine 2,3-dioxygenase-1 (IDO1) is the first and rate-limiting step in the synthesis of nicotinamide adenine dinucleotide (NAD) which is a critical co-factor involved in glycolysis and oxidative phosphorylation [ 71 ]. Immune suppression is triggered by a two-fold effect of IDO activity by first depleting Trp, and the accumulation of the immunosuppressive metabolite kynurenine (Kyn).…”

Section: Metabolitesmentioning

confidence: 99%

Fine-Tuning the Tumour Microenvironment: Current Perspectives on the Mechanisms of Tumour Immunosuppression

Armitage

Newnes

McDonnell

et al. 2021

Cells

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Immunotherapy has revolutionised the treatment of cancers by harnessing the power of the immune system to eradicate malignant tissue. However, it is well recognised that some cancers are highly resistant to these therapies, which is in part attributed to the immunosuppressive landscape of the tumour microenvironment (TME). The contexture of the TME is highly heterogeneous and contains a complex architecture of immune, stromal, vascular and tumour cells in addition to acellular components such as the extracellular matrix. While understanding the dynamics of the TME has been instrumental in predicting durable responses to immunotherapy and developing new treatment strategies, recent evidence challenges the fundamental paradigms of how tumours can effectively subvert immunosurveillance. Here, we discuss the various immunosuppressive features of the TME and how fine-tuning these mechanisms, rather than ablating them completely, may result in a more comprehensive and balanced anti-tumour response.

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Immunosuppressive IDO in Cancer: Mechanisms of Action, Animal Models, and Targeting Strategies

Abstract: converges on the central premise that maximal immunotherapeutic efficacy in subjects with advanced cancer requires both IDO enzyme-and non-enzyme-neutralization, which is not adequately addressed by available IDO-targeting pharmacologic approaches at this time.

Cited by 158 publications

References 119 publications

Wilms’ Tumor Primary Cells Display Potent Immunoregulatory Properties on NK Cells and Macrophages

Wilms’ Tumor Primary Cells Display Potent Immunoregulatory Properties on NK Cells and Macrophages

The Role of Tryptophan Metabolites in Musculoskeletal Stem Cell Aging

Fine-Tuning the Tumour Microenvironment: Current Perspectives on the Mechanisms of Tumour Immunosuppression

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