IDO and intra‐tumoral neutrophils were independent prognostic factors for overall survival for hepatocellular carcinoma

Wang, Yan; Yao, Rongrong; Zhang, Lan; Xie, Xiaoying; Chen, Rongxin; Ren, Zhenggang

doi:10.1002/jcla.22872

Cited by 16 publications

(11 citation statements)

References 32 publications

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“…In line with these findings, expression of AHR, together with IDO1, kynurenine, and PD-L1, correlated with poor prognosis in hepatocellular carcinoma patients [66]. Tissue microarray analysis of 153 HCC patients confirmed a negative correlation of IDO expression and overall survival [67]. Likewise, as a promoter of HCC proliferation and tumor invasion, TDO has also been suggested as a new prognostic biomarker of HCC [68].…”

Section: Ahr In Hepatocellular Carcinomasupporting

confidence: 54%

“…(D) Alcohol-induced liver injury: AHR activation reduces EtOH-induced oxidative stress, inflammation, and hepatocyte apoptosis [49,50]. (E) HCC: increased production of the AHR ligand kynurenine via TDO and IDO1 results in upregulation of PD-L1, impaired CD8 T cell responses, and tumor progression [65][66][67][68]. (F) Fibrosis: AHRdependent IL-17 and IL-22 production as well as AHR activation via IDO2/Kyn can promote liver fibrosis [56,57], while ITE-induced AHR activation in HSCs dampens liver fibrosis [54].…”

Section: Discussionmentioning

confidence: 99%

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The aryl hydrocarbon receptor in liver inflammation

Carambia

Schuran

2021

Semin Immunopathol

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The aryl hydrocarbon receptor (AHR) is a ubiquitously expressed ligand-activated transcription factor with multifaceted physiological functions. In the immune system, AHR has been unequivocally identified as a key regulatory factor that can integrate environmental, dietary, or microbial signals into innate and adaptive immune responses. Correspondingly, AHR activity seems to be most important at barrier organs, such as the gut, skin, and lung. The liver is likewise prominently exposed to gut-derived dietary or microbial AHR ligands and, moreover, generates plenty of AHR ligands itself. Yet, surprisingly little is known about the role of AHR in the regulation of hepatic immune responses, which are normally biased towards tolerance, preventing harmful inflammation in response to innocuous stimuli. In this review, we summarize the current knowledge about the role of AHR in hepatic immune responses in the healthy liver as well as in inflammatory liver disease. Moreover, we discuss AHR as a potential therapeutic target in hepatic disorders, including autoimmune liver disease, liver fibrosis, and liver cancer.

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Section: Ahr In Hepatocellular Carcinomasupporting

confidence: 54%

Section: Discussionmentioning

confidence: 99%

The aryl hydrocarbon receptor in liver inflammation

Carambia

Schuran

2021

Semin Immunopathol

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“…Although significance of our approach is the identification of correlation pattern by combination analysis, such an approach at protein levels is laborious and often limited with the sensitivity to demonstrate correlation. Nevertheless, our results were supported by previous studies which demonstrated that some B7 family molecules such as PD-L1 ( 64 , 65 ), PD-L2 ( 66 ), PD-1 ( 67 ), B7-H2 ( 68 ), B7-H3 ( 69 ) and IDO ( 70 ) play a significant functional role in modulating anti-HCC immunity. Although we have demonstrated the synergistic functions of IDO and PD-L1, future studies are necessary to determine if the other identified correlation of costimulatory and coinhibitory molecules play a functional synergistic role in modulating anti-HCC immunity.…”

Section: Discussionsupporting

confidence: 90%

Correlation Patterns Among B7 Family Ligands and Tryptophan Degrading Enzymes in Hepatocellular Carcinoma

et al. 2020

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Mechanisms of dysfunctional T cell immunity in Hepatocellular Carcinoma (HCC) need to be well defined. B7 family molecules provide both co-stimulatory and co-inhibitory signals to T cells while tryptophan degrading enzymes like Indoleamine 2,3 dioxygenase (IDO) and Tryptophan 2,3 Dioxygenase (TDO) mediate tumor immune tolerance. It is necessary to identify their in situ correlative expression, which informs targets for combined immunotherapy approaches. We investigated B7 family molecules, IDO, TDO and immune responsive effectors in the tumor tissues of patients with HCC (n = 28) using a pathway-focused quantitative nanoscale chip real-time PCR. Four best correlative expressions, namely (1) B7-1 & PD-L2, (2) B7-H2 & B7-H3, (3) B7-2 & PD-L1, (4) PD-L1 & PD-L2, were identified among B7 family ligands, albeit they express at different levels. Although TDO expression is higher than IDO, PD-L1 correlates only with IDO but not TDO. Immune effector (Granzyme B) and suppressive (PD-1 and TGF-β) genes correlate with IDO and B7-1, B7-H5, PD-L2. Identification of the in situ correlation of PD-L1, PD-L2 and IDO suggest their cumulative immuno suppressive role in HCC. The distinct correlations among B7-1, B7-2, B7-H2, and B7-H3, correlation of PD-1 with non-cognate ligands such as B7-1 and B7-H5, and correlation of tumor lytic enzyme Granzyme B with IDO and PD-L2 suggest that HCC microenvironment is complexly orchestrated with both stimulatory and inhibitory molecules which together neutralize and blunt anti-HCC immunity. Functional assays demonstrate that both PDL-1 and IDO synergistically inhibit T cell responses. Altogether, the present data suggest the usage of combined immune checkpoint blocking strategies targeting co-inhibitory B7 molecules and IDO for HCC management.

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“…Several reports indicate that IDO-1 expression is increased in human cancer tissues and patient follow up studies reveal that IDO-1 expression is associated with patient outcome [67,68]. In a prospective study of hepatocellular cancer patients, tissue IDO expression is negatively associated with patient survival: a high IDO expression is an independent prognostic factor for poor overall survival [69]. Tumor TDO overexpression was reported to be associated with poor survival in patients with breast cancer [70] and hepatocellular cancer [71].…”

Section: Tryptophan Catabolic Enzymes As Prognostic Biomarkers Of Cancermentioning

confidence: 99%

Tryptophan Metabolism and Cancer Progression

2021

J. Anal. Oncol.

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Intracellular tryptophan (Trp) is catabolized to a large repertoire of metabolites via two major pathways: indoleamine and tryptophan 2, 3-dioxygenases (IDO/TDO) and Trp hydroxylase (TPH) pathways. The catabolites possess diverse biological activities and carry out various physiological functions. Several catabolites such as kynurenine (Kyn) and serotonin promote while melatonin and 5-methoxytryptophan (5-MTP) suppress cancer growth and metastasis. Cancer cell-derived Kyn enhances cancer growth and evasion of immunosurveillance by interacting with cancer cell and immune cell membrane aryl hydrocarbon receptors (AHR), respectively. Serotonin exerts its tumorpromoting activities through type 1 and type 2 serotonin receptors. 5-MTP and melatonin suppress cancer growth and metastasis by common mechanisms, i.e., inhibition of p300 histone acetyltransferase (HAT) and NF-κB activation, and suppression of cyclooxygenase-2 and cytokine transcription. Both metabolites block p38 MAPK signaling pathway. Human cancer tissues express increased levels of IDO, TDO and kynurenine monooxygenase (KMO) which are correlated with reduced patient survival. In summary, cancer Trp metabolism regulates cancer growth and metastasis by complex mechanisms. 5-MTP and melatonin provide valuable lead to develop new drugs for chemo-prevention and adjuvant therapy of cancer.

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IDO and intra‐tumoral neutrophils were independent prognostic factors for overall survival for hepatocellular carcinoma

Cited by 16 publications

References 32 publications

The aryl hydrocarbon receptor in liver inflammation

The aryl hydrocarbon receptor in liver inflammation

Correlation Patterns Among B7 Family Ligands and Tryptophan Degrading Enzymes in Hepatocellular Carcinoma

Tryptophan Metabolism and Cancer Progression

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