Chronic inflammation that facilitates tumor progression creates local immune suppression by inducing indoleamine 2,3 dioxygenase

Muller, Alexander J.; Sharma, Madhav; Chandler, Phillip; DuHadaway, James B.; Everhart, Mary E.; Johnson, Burles A.; Kahler, David J.; Pihkala, Jeanene; Soler, Aléjandro Peralta; Munn, David H.; Prendergast, George C.; Mellor, Andrew L.

doi:10.1073/pnas.0806173105

Cited by 218 publications

(237 citation statements)

References 47 publications

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“…It has been shown in several studies that sera from cancer patients have higher kynurenine/tryptophan ratios than sera from normal volunteers, consistent with increased IDO activity (16,18,19). In preclinical models, Ido1 expression by immunogenic tumors prevents rejection (14), silencing of IDO expression in tumor cells enhances tumor-specific killing (20), and the incidence and growth of 7,12-dimethylbenz (a)anthracene-induced premalignant skin papillomas is decreased in Ido1 −/− mice (21). Taken together, these data suggest that modulating kynurenine generation through IDO inhibition might prove beneficial to cancer patients.…”

Section: Introductionmentioning

confidence: 87%

Hydroxyamidine Inhibitors of Indoleamine-2,3-dioxygenase Potently Suppress Systemic Tryptophan Catabolism and the Growth of IDO-Expressing Tumors

Koblish

Hansbury

Bowman

et al. 2010

Molecular Cancer Therapeutics

238

191

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Malignant tumors arise, in part, because the immune system does not adequately recognize and destroy them. Expression of indoleamine-2,3-dioxygenase (IDO; IDO1), a rate-limiting enzyme in the catabolism of tryptophan into kynurenine, contributes to this immune evasion. Here we describe the effects of systemic IDO inhibition using orally active hydroxyamidine small molecule inhibitors. A single dose of INCB023843 or INCB024360 results in efficient and durable suppression of Ido1 activity in the plasma of treated mice and dogs, the former to levels seen in Ido1-deficient mice. Hydroxyamidines potently suppress tryptophan metabolism in vitro in CT26 colon carcinoma and PAN02 pancreatic carcinoma cells and in vivo in tumors and their draining lymph nodes. Repeated administration of these IDO1 inhibitors impedes tumor growth in a dose-and lymphocyte-dependent fashion and is well tolerated in efficacy and preclinical toxicology studies. Substantiating the fundamental role of tumor cell-derived IDO expression, hydroxyamidines control the growth of IDO-expressing tumors in Ido1-deficient mice. These activities can be attributed, at least partially, to the increased immunoreactivity of lymphocytes found in tumors and their draining lymph nodes and to the reduction in tumor-associated regulatory T cells. INCB024360, a potent IDO1 inhibitor with desirable pharmaceutical properties, is poised to start clinical trials in cancer patients. Mol Cancer Ther; 9(2); 489-98.

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Section: Introductionmentioning

confidence: 87%

Hydroxyamidine Inhibitors of Indoleamine-2,3-dioxygenase Potently Suppress Systemic Tryptophan Catabolism and the Growth of IDO-Expressing Tumors

Koblish

Hansbury

Bowman

et al. 2010

Molecular Cancer Therapeutics

238

191

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“…Moreover, small cohorts of IDO-expressing cells mediate potent T-cell regulation that may predominate over a large excess of T-cell stimulatory DCs. Splenic IDO-competent cells closely resemble IDO-expressing cells in inflamed LNdraining sites of tumor growth and topical tumor promoter application, and these cells have been implicated in tumor progression and resistance to antitumor immunity (23,24,33).…”

Section: Discussionmentioning

confidence: 99%

“…S2H). However, IDOexpressing cells in inflamed tumor-draining lymph nodes (LNs), and LNs draining skin exposed to tumor promoters, closely resembled splenic IDO-competent cells (23,24).…”

Section: B Cells | T-cell Regulation | Cd19mentioning

confidence: 99%

B-lymphoid cells with attributes of dendritic cells regulate T cells via indoleamine 2,3-dioxygenase

Johnson¹,

Kahler²,

Baban³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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A discrete population of splenocytes with attributes of dendritic cells (DCs) and coexpressing the B-cell marker CD19 is uniquely competent to express the T-cell regulatory enzyme indoleamine 2,3-dioxygenase (IDO) in mice treated with TLR9 ligands (CpGs). Here we show that IDO-competent cells express the B-lineage commitment factor Pax5 and surface immunoglobulins. CD19 ablation abrogated IDO-dependent T-cell suppression by DCs, even though cells with phenotypic attributes matching IDO-competent cells developed normally and expressed IDO in response to interferon γ. Consequently, DCs and regulatory T cells (Tregs) did not acquire T-cell regulatory functions after TLR9 ligation, providing an alternative perspective on the known T-cell regulatory defects of CD19-deficient mice. DCs from B-cell-deficient mice expressed IDO and mediated T-cell suppression after TLR9 ligation, indicating that B-cell attributes were not essential for B-lymphoid IDO-competent cells to regulate T cells. Thus, IDO-competent cells constitute a distinctive B-lymphoid cell type with quintessential T-cell regulatory attributes and phenotypic features of both B cells and DCs. B cells | T-cell regulation | CD19I ndoleamine 2,3-dioxygenase (IDO) is an intracellular enzyme expressed in response to interferons (IFNs) at sites of inflammation. IDO inhibitors exacerbated T-cell-mediated pathology in models of tumor growth and autoimmune, infectious, and allergic diseases, and are currently under evaluation as potential tumor vaccine adjuvants in clinical settings (1, 2). By analogy to the tumor-protective effects of IDO, some pathogens may exploit IDO to facilitate persistence and IDO may attenuate vaccine-induced immunity (3-6). Consistent with this paradigm, artificially enhanced IDO activity attenuated graft versus host disease after bone marrow engraftment and prolonged rat lung allograft survival (7-9). Thus, IDO-dependent T-cell regulation occurs in multiple settings of chronic inflammation relevant to clinical syndromes.Despite the potential benefits of manipulating IDO activity to improve therapy in chronic inflammatory syndromes, little is known about the cellular basis of IDO-mediated T-cell regulation in physiologic settings. Antigen presenting cells (APCs) expressing IDO, such as dendritic cells (DCs), activate regulatory T cells (Tregs) and directly suppress effector T cells at sites of tissue inflammation (10, 11). Cells with functional and phenotypic attributes of DCs in mice and humans are competent to express IDO and regulate T-cell responses (11-15). In mice, splenocytes uniquely competent to mediate T-cell suppression via IDO after in vivo treatment with TLR9 ligands (CpGs) were a rare cell type located in splenic red pulp with phenotypic attributes of DCs (CD11c, CD8α, CD80/86, MHCII). IDO-competent cells also expressed B220 and the B-cell lineage marker CD19, but not the plasmacytoid DC (pDC) marker PDCA/120G8 (13). After CTLA4-Ig and CpG treatment, IDO-competent cells produced IFNα (15, 16), a functional attribute of pDCs and ...

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“…11a-c). In a broader context, a significant number of malignancies arise from areas of mostly chronic infection and inflammation 33 , where Trp catabolism in the tumour microenvironment is activated and sustains local immune suppression 34 . Activation of the AHR by Kyn generated in response to inflammatory stimuli may thus constitute a previously unrecognized pathway connecting inflammation and carcinogenesis.…”

Section: Article Researchmentioning

confidence: 99%

An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor

Opitz

Litzenburger

Sahm

et al. 2011

Nature

1,597

1,534

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Chronic inflammation that facilitates tumor progression creates local immune suppression by inducing indoleamine 2,3 dioxygenase

Cited by 218 publications

References 47 publications

Hydroxyamidine Inhibitors of Indoleamine-2,3-dioxygenase Potently Suppress Systemic Tryptophan Catabolism and the Growth of IDO-Expressing Tumors

Hydroxyamidine Inhibitors of Indoleamine-2,3-dioxygenase Potently Suppress Systemic Tryptophan Catabolism and the Growth of IDO-Expressing Tumors

B-lymphoid cells with attributes of dendritic cells regulate T cells via indoleamine 2,3-dioxygenase

An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor

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