Tumor Cell IDO Enhances Immune Suppression and Decreases Survival Independent of Tryptophan Metabolism in Glioblastoma

Zhai, Lijie; Bell, April; Ladomersky, Erik; Lauing, Kristen L.; Bollu, Lakshmi Reddy; Nguyen, Brenda; Genet, Matthew; Kim, Miri; Chen, Peiwen; Mi, Xinlei; Wu, Jennifer D.; Schipma, Matthew J.; Wray, Brian; Griffiths, John R.; Unwin, Richard D.; Clark, Simon J.; Acharya, Rajesh; Bao, Riyue; Horbinski, Craig; Lukas, Rimas V.; Schiltz, Gary E.; Wainwright, Derek A.

doi:10.1158/1078-0432.ccr-21-1392

Cited by 67 publications

(73 citation statements)

References 42 publications

(46 reference statements)

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“…Additionally, according to the fact that compared to the physiological situation systemic Kyn decreases while intratumoral Kyn increases in GBM patients, exploration on Kyn pathway modulation is still in its infancy [ 218 ]. Nevertheless, recent study has found that IDO induces the expression of complement factor H (CFH) and its isoform, factor H like protein 1 (FHL-1) independent of its enzymatic activity, which contributes to poor survival of GBM patients [ 219 ]. This finding would help explore the novel targets of IDO inhibition.…”

Section: Glioblastomamentioning

confidence: 99%

Glioma targeted therapy: insight into future of molecular approaches

et al. 2022

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Gliomas are the common type of brain tumors originating from glial cells. Epidemiologically, gliomas occur among all ages, more often seen in adults, which males are more susceptible than females. According to the fifth edition of the WHO Classification of Tumors of the Central Nervous System (WHO CNS5), standard of care and prognosis of gliomas can be dramatically different. Generally, circumscribed gliomas are usually benign and recommended to early complete resection, with chemotherapy if necessary. Diffuse gliomas and other high-grade gliomas according to their molecule subtype are slightly intractable, with necessity of chemotherapy. However, for glioblastoma, feasible resection followed by radiotherapy plus temozolomide chemotherapy define the current standard of care. Here, we discuss novel feasible or potential targets for treatment of gliomas, especially IDH-wild type glioblastoma. Classic targets such as the p53 and retinoblastoma (RB) pathway and epidermal growth factor receptor (EGFR) gene alteration have met failure due to complex regulatory network. There is ever-increasing interest in immunotherapy (immune checkpoint molecule, tumor associated macrophage, dendritic cell vaccine, CAR-T), tumor microenvironment, and combination of several efficacious methods. With many targeted therapy options emerging, biomarkers guiding the prescription of a particular targeted therapy are also attractive. More pre-clinical and clinical trials are urgently needed to explore and evaluate the feasibility of targeted therapy with the corresponding biomarkers for effective personalized treatment options.

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Section: Glioblastomamentioning

confidence: 99%

Glioma targeted therapy: insight into future of molecular approaches

et al. 2022

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“…A tryptophan metabolic enzyme, IDO is also considered a contributing factor for immune resistance in GBM through tryptophan metabolism. A recent study has shown that IDO can have shown that IDO can suppress immune response by inducing the expression of compliment factor H (CFH) independent of tryptophan metabolism and could act as a potential target for therapy ( 52 ).…”

Section: Current Immunotherapies For Gbmmentioning

confidence: 99%

Interactions Between Anti-Angiogenic Therapy and Immunotherapy in Glioblastoma

2022

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Glioblastoma is the most aggressive brain tumor with a median survival ranging from 6.2 to 16.7 months. The complex interactions between the tumor and the cells of tumor microenvironment leads to tumor evolution which ultimately results in treatment failure. Immunotherapy has shown great potential in the treatment of solid tumors but has been less effective in treating glioblastoma. Failure of immunotherapy in glioblastoma has been attributed to low T-cell infiltration in glioblastoma and dysfunction of the T-cells that are present in the glioblastoma microenvironment. Recent advances in single-cell sequencing have increased our understanding of the transcriptional changes in the tumor microenvironment pre and post-treatment. Another treatment modality targeting the tumor microenvironment that has failed in glioblastoma has been anti-angiogenic therapy such as the VEGF neutralizing antibody bevacizumab, which did not improve survival in randomized clinical trials. Interestingly, the immunosuppressed microenvironment and abnormal vasculature of glioblastoma interact in ways that suggest the potential for synergy between these two therapeutic modalities that have failed individually. Abnormal tumor vasculature has been associated with immune evasion and the creation of an immunosuppressive microenvironment, suggesting that inhibiting pro-angiogenic factors like VEGF can increase infiltration of effector immune cells into the tumor microenvironment. Remodeling of the tumor vasculature by inhibiting VEGFR2 has also been shown to improve the efficacy of PDL1 cancer immunotherapy in mouse models of different cancers. In this review, we discuss the recent developments in our understanding of the glioblastoma tumor microenvironment specially the tumor vasculature and its interactions with the immune cells, and opportunities to target these interactions therapeutically. Combining anti-angiogenic and immunotherapy in glioblastoma has the potential to unlock these therapeutic modalities and impact the survival of patients with this devastating cancer.

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“…showed that in tumor cells, IDO1 suppressed the antitumor immune response by increasing the expression of complement factor H (CFH) and factor H-like protein 1 (FHL-1) instead of its association with Trp metabolism in human glioblastoma, and there was a survival advantage mediated by ICIs requiring non-tumor cell IDO1 enzyme activity in mouse glioblastoma. Oppositely, the combination of radiation and PD-1 antibody treatment efficacy required to inhibit IDO1 enzyme activity in non-tumor cells from another study of mouse glioblastoma model ( 97 , 108 , 109 ). The reason for the controversial conclusion may be that the immunosuppressive effects of IDO1 in the organism are not isolated, and there are multiple factors involved, such as the differentiation degree, the invasion degree, lymph node metastasis, clinical stage of the tumor, the different combinations of inhibitors, the infiltration of T effector cells in the tumor lesion, the host cell IDO1 origin, the enzyme activity versus non-enzyme effects of IDO1 in tumor lesion or TDLN, and age of the subject, all of which need to be considered comprehensively in order to better apply and develop IDO1-targeted drug and new combined therapeutic strategies in the clinical setting.…”

Section: The Significance Of Targeting Indoleamine 23-dioxygenase 1 In Tumor Therapymentioning

confidence: 99%

“…In fact, the consumption of Trp and the accumulation of Kyn do not always happen simultaneously in human cancers, and the immunosuppression effects of IDO1 in TME do not just depend on its enzyme activity. On the contrary, its enzyme activity may also contribute to the response to ICI therapy ( 97 , 108 , 129 , 130 ). Therefore, the high IDO1 expression is not a single indicator to decide whether to choose IDO1 inhibitors, and the IDO1 activity assessment may also need multiple factors, including the concentrations of Trp and Kyn as well as the Kyn/Trp ratio in human cancers.…”

Section: The Significance Of Targeting Indoleamine 23-dioxygenase 1 In Tumor Therapymentioning

confidence: 99%

Indoleamine 2,3-Dioxygenase 1: A Promising Therapeutic Target in Malignant Tumor

Song

et al. 2021

Front. Immunol.

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Tumorigenesis is a complex multifactorial and multistep process in which tumors can utilize a diverse repertoire of immunosuppressive mechanisms to evade host immune attacks. The degradation of tryptophan into immunosuppressive kynurenine is considered an important immunosuppressive mechanism in the tumor microenvironment. There are three enzymes, namely, tryptophan 2,3-dioxygenase (TDO), indoleamine 2,3-dioxygenase 1 (IDO1), and indoleamine 2,3-dioxygenase 2 (IDO2), involved in the metabolism of tryptophan. IDO1 has a wider distribution and higher activity in catalyzing tryptophan than the other two; therefore, it has been studied most extensively. IDO1 is a cytosolic monomeric, heme-containing enzyme, which is now considered an authentic immune regulator and represents one of the promising drug targets for tumor immunotherapy. Collectively, this review highlights the regulation of IDO1 gene expression and the ambivalent mechanisms of IDO1 on the antitumoral immune response. Further, new therapeutic targets via the regulation of IDO1 are discussed. A comprehensive analysis of the expression and biological function of IDO1 can help us to understand the therapeutic strategies of the inhibitors targeting IDO1 in malignant tumors.

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Tumor Cell IDO Enhances Immune Suppression and Decreases Survival Independent of Tryptophan Metabolism in Glioblastoma

Cited by 67 publications

References 42 publications

Glioma targeted therapy: insight into future of molecular approaches

Glioma targeted therapy: insight into future of molecular approaches

Interactions Between Anti-Angiogenic Therapy and Immunotherapy in Glioblastoma

Indoleamine 2,3-Dioxygenase 1: A Promising Therapeutic Target in Malignant Tumor

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