Selective inhibition of IDO1 effectively regulates mediators of antitumor immunity

Liu, Xiangdong; Shin, Niu; Koblish, Holly K.; Yang, Gengjie; Wang, Qian; Wang, Kathy; Leffet, Lynn; Hansbury, Michael; Thomas, Beth Ann; Rupar, Mark; Waeltz, Paul; Bowman, Kevin; Polam, Padmaja; Sparks, Richard B.; Yue, Eddy W.; Li, Yanlong; Wynn, Richard; Fridman, Jordan S.; Burn, Timothy C.; Combs, Andrew P.; Newton, Robert; Scherle, Peggy

doi:10.1182/blood-2009-09-246124

Cited by 490 publications

(383 citation statements)

References 51 publications

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“…Independent from its catalytic potential, IDO1 was shown in murine experiments to act as a signaling molecule in TGFb-mediated immune suppression (12). Taken together, these observations provide a strong rationale for the clinical development in oncology of drugs that inhibit IDO1 and more particularly its catalytic activity, alone or in combination with other immunotherapy approaches such as CTLA4-blocking agents (13). Such IDO1 inhibitors are currently in the early phases of clinical testing.…”

Section: Introductionmentioning

confidence: 92%

Extensive Profiling of the Expression of the Indoleamine 2,3-Dioxygenase 1 Protein in Normal and Tumoral Human Tissues

Théate

Baren

Pilotte

et al. 2015

Cancer Immunology Research

308

295

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Tryptophan catabolism by indoleamine 2,3-dioxygenase 1 (IDO1) plays a key role in tumoral resistance to immune rejection. In humans, constitutive expression of IDO1 has been observed in several tumor types. However, a comprehensive analysis of its expression in normal and tumor tissues is still required to anticipate the risks and potential benefits of IDO1 inhibitors. Using a newly validated monoclonal antibody to human IDO1, we performed an extensive immunohistochemical analysis of IDO1 expression in normal and tumor tissues. In normal tissues, IDO1 was expressed by endothelial cells in the placenta and lung and by epithelial cells in the female genital tract. In lymphoid tissues, IDO1 was expressed in mature dendritic cells with a phenotype (CD83 þ ,

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Section: Introductionmentioning

confidence: 92%

Extensive Profiling of the Expression of the Indoleamine 2,3-Dioxygenase 1 Protein in Normal and Tumoral Human Tissues

Théate

Baren

Pilotte

et al. 2015

Cancer Immunology Research

308

295

View full text Add to dashboard Cite

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“…In keeping with these findings, clinical trials are currently underway for competitive IDO inhibitors. 59,60 Logically, Trp depletion from the tumor microenvironment should impair protein synthesis in neoplastic cells. However, IDO-1-expressing cells may be protected from Trp self-starvation by increasing the expression of tryptophanyl-tRNA-synthetase (tRNA(trp) or WARS).…”

Section: Discussionmentioning

confidence: 99%

Medullary carcinoma of the colon: a distinct morphology reveals a distinctive immunoregulatory microenvironment

Friedman

Brodsky

et al. 2016

Modern Pathology

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Medullary carcinoma of the colon is a unique histologic subtype of microsatellite unstable colorectal carcinoma but little is known regarding its tumor-immunoregulatory microenvironment. The aims of this study were to characterize the immune environment of medullary carcinoma and compare it with other microsatellite unstable and microsatellite stable colorectal carcinomas. An initial gene expression microarray analysis of six cases of medullary carcinoma was used to detect potentially differentially expressed genes. We extended this analysis utilizing genomic data from the Cancer Genome Atlas to compare eight cases of medullary carcinoma with other microsatellite unstable and stable carcinomas. Finally, we evaluated expression of key immune pathway proteins and lymphocyte subsets via immunohistochemistry of a large group of medullary carcinomas (n = 105) and compared these findings with three other groups: poorly differentiated, microsatellite unstable well-differentiated and microsatellite stable well-differentiated carcinomas. Microarray and the Cancer Genome Atlas data analysis identified significant upregulation of several immunoregulatory genes induced by IFNγ including IDO-1, WARS (tRNA(trp)), GBP1, GBP4, GBP5, PDCD1 (PD-1), and CD274 (PD-L1) in medullary carcinoma compared with other microsatellite unstable and microsatellite stable tumors. By immunohistochemistry, IDO-1 was expressed in 64% of medullary carcinomas compared with 19% (9/47) of poorly differentiated carcinomas, 14% (3/22) of microsatellite unstable, and 7% (2/30) of the microsatellite stable well-differentiated carcinomas (Po 0.0001). tRNA(trp) was overexpressed in 81% (84/104) of medullary carcinomas, 19% (9/47) of poorly differentiated, 32% (7/22) of microsatellite unstable, and 3% (1/30) of microsatellite stable well-differentiated carcinomas (Po 0.0001). Medullary carcinoma had higher mean CD8+ and PD-L1+ tumor-infiltrating lymphocytes compared with all other groups (P o0.0001). This study demonstrates overexpression of several immunoregulatory genes in microsatellite unstable colorectal carcinomas and that expression of these genes and proteins is more prevalent in the medullary carcinoma subtype, which may be of use both diagnostically and therapeutically.

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“…To inhibit Indoleamine-2,3-dioxygenase 1 (IDO1), a potent (both human and murine) and selective IDO1 inhibitor (hereafter IDOInh) was synthesized informed by previous studies that investigated IDO1 inhibition as a potential immunotherapeutic strategy for cancer treatment (see Liu et al, 2010;Yue et al, 2009). The in vitro effective concentration on murine IDO1 to achieve a 50% reduction in KYN synthesis (EC 50 ) in a cellular assay was 390 nM.…”

Section: Cd40ab  Ido Inhibitor On Saccharin Drinking and Levels Of Cmentioning

confidence: 99%

CD40-TNF activation in mice induces extended sickness behavior syndrome co-incident with but not dependent on activation of the kynurenine pathway

Cathomas

Fuertig

Sigrist

et al. 2015

Brain, Behavior, and Immunity

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The similarity between sickness behavior syndrome (SBS) in infection and autoimmune disorders and certain symptoms in major depressive disorder (MDD), and the high co-morbidity of autoimmune disorders and MDD, constitutes some of the major evidence for the immune-inflammation hypothesis of MDD. CD40 ligand-CD40 immune-activation is important in host response to infection and in development of autoimmunity. Mice given a single intra-peritoneal injection of CD40 agonist antibody (CD40AB) develop SBS for 2-3days characterized by weight loss and increased sleep, effects that are dependent on the cytokine, tumor necrosis factor (TNF). Here we report that CD40AB also induces behavioral effects that extend beyond acute SBS and co-occur with but are not mediated by kynurenine pathway activation and recovery. CD40AB led to decreased saccharin drinking (days 1-7) and decreased Pavlovian fear conditioning (days 5-6), and was without effect on physical fatigue (day 5). These behavioral effects co-occurred with increased plasma and brain levels of kynurenine and its metabolites (days 1-7/8). Co-injection of TNF blocker etanercept with CD40AB prevented each of SBS, reduced saccharin drinking, and kynurenine pathway activation in plasma and brain. Repeated oral administration of a selective indoleamine 2,3-dioxygenase (IDO) inhibitor blocked activation of the kynurenine pathway but was without effect on SBS and saccharin drinking. This study provides novel evidence that CD40-TNF activation induces deficits in saccharin drinking and Pavlovian fear learning and activates the kynurenine pathway, and that CD40-TNF activation of the kynurenine pathway is not necessary for induction of the acute or extended SBS effects. AbstractThe similarity between sickness behavior syndrome (SBS) in infection and autoimmune disorders and certain symptoms in major depressive disorder (MDD), and the high co-morbidity of autoimmune disorders and MDD, constitutes some of the major evidence for the immuneinflammation hypothesis of MDD. CD40 ligand-CD40 immune-activation is important in host response to infection and in development of autoimmunity. Mice given a single intra-peritoneal injection of CD40 agonist antibody (CD40AB) develop SBS for 2-3 days characterized by weight loss and increased sleep, effects that are dependent on the cytokine, tumor necrosis factor (TNF). Here we report that CD40AB also induces behavioral effects that extend beyond acute SBS and co-occur with but are not mediated by kynurenine pathway activation and recovery. CD40AB led to decreased saccharin drinking (days 1-7) and decreased Pavlovian fear conditioning (days 5-6), and was without effect on physical fatigue (day 5). These behavioral effects co-occurred with increased plasma and brain levels of kynurenine and its metabolites (days 1-7/8). Co-injection of TNF blocker etanercept with CD40AB prevented each of SBS, reduced saccharin drinking, and kynurenine pathway activation in plasma and brain. Repeated oral administration of a selective indoleamine 2,3-dioxyg...

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Selective inhibition of IDO1 effectively regulates mediators of antitumor immunity

Cited by 490 publications

References 51 publications

Extensive Profiling of the Expression of the Indoleamine 2,3-Dioxygenase 1 Protein in Normal and Tumoral Human Tissues

Extensive Profiling of the Expression of the Indoleamine 2,3-Dioxygenase 1 Protein in Normal and Tumoral Human Tissues

Medullary carcinoma of the colon: a distinct morphology reveals a distinctive immunoregulatory microenvironment

CD40-TNF activation in mice induces extended sickness behavior syndrome co-incident with but not dependent on activation of the kynurenine pathway

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