Expression of Indoleamine 2,3-Dioxygenase in Metastatic Pancreatic Ductal Adenocarcinoma Recruits Regulatory T Cells to Avoid Immune Detection

Witkiewicz, Agnieszka K.; Williams, Timothy K.; Cozzitorto, Joseph A.; Durkan, Brandice; Showalter, Shayna L.; Yeo, Charles J.; Brody, Jonathan R.

doi:10.1016/j.jamcollsurg.2007.12.014

Cited by 141 publications

(100 citation statements)

References 19 publications

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“…8,14 Increased expression of IDO1 has been shown to be an independent prognostic variable for reduced survival in patients with acute myeloid leukemia (AML), small-cell lung, melanoma, ovarian, colorectal, pancreatic, and endometrial cancers. [14][15][16][17][18][19][20][21] The aforementioned findings clearly support the role of IDO1 in immunosuppression and tumor escape. However, the interpretation of some experiments conducted primarily with 1MT has been questioned.…”

Section: Introductionsupporting

confidence: 66%

Selective inhibition of IDO1 effectively regulates mediators of antitumor immunity

Liu

Shin

Koblish

et al. 2010

Blood

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361

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Section: Introductionsupporting

confidence: 66%

Selective inhibition of IDO1 effectively regulates mediators of antitumor immunity

Liu

Shin

Koblish

et al. 2010

Blood

490

361

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“…The above considerations approached toward the former. However, the latter is also hypothetically possible, because the accumulation of kynurenine metabolites in blood and tissues may result from excessive immune stimulation by a more aggressive disease, as was demonstrated in infective, autoimmune and malignant diseases (Witkiewicz et al, 2008;Lob et al, 2009). Another theory speculated that KYNA is an effector constituent of an immune feedback control loop.…”

Section: Discussionmentioning

confidence: 99%

Serum Kynurenic Acid: Possible Association with Invasiveness of Non-small Cell Lung Cancer

Sagan

Kocki²,

Kocki³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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The lung adenocarcinoma is considered more aggressive than other types of non-small cell lung cancer. As metabolites of tryptophan degradation along the kynurenine pathway, including kynurenic acid, have been shown to induce immunosuppression and facilitate escape of tumor cells from immune surveillance, a hypothesis was set up that differences in biological behavior between types of lung cancer may be associated with altered activity of the kynurenine metabolic pathway. The aim of the study was to determine kynurenic acid levels in the serum of patients with bronchial adenocarcinoma for comparison with other types of non-small cell lung cancer. A total of 227 patients with non-small cell lung cancer were enrolled in the study, including 71 with adenocarcinoma and 96 with squamous cell carcinoma. Serum kynurenic acid concentration was determined with use of high performance liquid chromatography and fluorometry. The level of kynurenic acid in the serum of patients with adenocarcinoma was significantly higher than in those with squamous cell lung cancer (107.1 ± 62.8 pmol/ml; 95%CI: 92.4 to 132.3 pmol/ml versus 82.1 ± 47.6 pmol/ml; 95%CI: 78.5 to 91.2 pmol/ml, respectively; p = 0.027). Differences between other histological types of lung cancer were insignificant. We conclude that increased activity of kynurenine metabolic pathway manifested by elevated serum kynurenic acid level may be one of the factors associated with clinically distinct biological behavior of adenocarcinoma, in particular high invasiveness and rapid progression.

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“…One ongoing trial is testing the use of IDO inhibitors in PDAC. IDO is a tryptophan-metabolizing enzyme targeting the kynurenine pathway, whose products, tryptophan metabolites, are toxic to effector T cells, thereby creating an immunosuppressive microenvironment in tumors by increasing T reg cell survival (Witkiewicz et al 2008;Lob et al 2009). Moreover, studies show that IDO expression in PDAC is associated with poor disease outcome and correlates with aggressive disease progression (Godin-Ethier et al 2011).…”

Section: Prospect Of Pdac Immunotherapymentioning

confidence: 99%

Genetics and biology of pancreatic ductal adenocarcinoma

et al. 2016

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With 5-year survival rates remaining constant at 6% and rising incidences associated with an epidemic in obesity and metabolic syndrome, pancreatic ductal adenocarcinoma (PDAC) is on track to become the second most common cause of cancer-related deaths by 2030. The high mortality rate of PDAC stems primarily from the lack of early diagnosis and ineffective treatment for advanced tumors. During the past decade, the comprehensive atlas of genomic alterations, the prominence of specific pathways, the preclinical validation of such emerging targets, sophisticated preclinical model systems, and the molecular classification of PDAC into specific disease subtypes have all converged to illuminate drug discovery programs with clearer clinical path hypotheses. A deeper understanding of cancer cell biology, particularly altered cancer cell metabolism and impaired DNA repair processes, is providing novel therapeutic strategies that show strong preclinical activity. Elucidation of tumor biology principles, most notably a deeper understanding of the complexity of immune regulation in the tumor microenvironment, has provided an exciting framework to reawaken the immune system to attack PDAC cancer cells. While the long road of translation lies ahead, the path to meaningful clinical progress has never been clearer to improve PDAC patient survival. Pancreatic ductal adenocarcinoma (PDAC) pathogenesisOn gross inspection, PDAC presents as a poorly demarcated, firm white-yellow mass, with the surrounding nonmalignant pancreas typically showing atrophy, fibrosis, and dilated ducts due to the obstructive effects of expanding carcinoma. Microscopically, these neoplasms vary from well-differentiated gland-forming carcinomas to poorly differentiated "sarcomatoid" carcinomas diagnosed only upon immunolabeling due to predominant mesenchymal features (Hruban et al. 2007). PDAC evolves from well-defined precursor lesions that, in the context of their genetic features, define the genetic progression model of pancreatic carcinogenesis (Yachida et al. 2010). Early disease histology manifests as several distinct types of precursor lesions-the most common are microscopic pancreatic intraepithelial neoplasia (PanIN), followed by the macroscopic cysts; namely, the intraductal papillary mucinous neoplasm (IPMN) and mucinous cystic neoplasm (MCN) (Matthaei et al. 2011). Since most PDAC cases become clinically apparent at advanced stages, major opportunities to reduce mortality rest with diagnostics and treatments that would enable the reliable identification and elimination of high-risk precursor lesions. Thus, the identification of these precursor lesions has provided an essential framework to define the genomic features that drive progression to advanced disease and develop effective screening and targeted therapeutics for earlier stage disease (Eser et al. 2011).The noninvasive PanIN lesions were formerly classified into three grades according to the extent of cytological and architectural atypia: PanIN1A (flat lesion) and PanIN1B (micropapillary...

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Expression of Indoleamine 2,3-Dioxygenase in Metastatic Pancreatic Ductal Adenocarcinoma Recruits Regulatory T Cells to Avoid Immune Detection

Cited by 141 publications

References 19 publications

Selective inhibition of IDO1 effectively regulates mediators of antitumor immunity

Selective inhibition of IDO1 effectively regulates mediators of antitumor immunity

Serum Kynurenic Acid: Possible Association with Invasiveness of Non-small Cell Lung Cancer

Genetics and biology of pancreatic ductal adenocarcinoma

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