Plasmacytoid dendritic cells from mouse tumor-draining lymph nodes directly activate mature Tregs via indoleamine 2,3-dioxygenase

Sharma, Madhav; Baban, Babak; Chandler, Phillip; Hou, De Yan; Singh, Nagendra; Yagita, Hideo; Azuma, Miyuki; Blazar, Bruce R.; Mellor, Andrew L.; Munn, David H.

doi:10.1172/jci31911

Cited by 720 publications

(739 citation statements)

References 54 publications

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“…In support, high levels of ICOSL promote survival, expansion, and IL-10-producing Tregs (31), converting Ag-specific T cell proliferation (32). Similarly, PD-L1 facilitates cell contact between pDCs and Tregs (22). Thus, our data support the finding that nonactivated pDCs (with an immature phenotype) can favor latent chronic inflammation induced by low-dose LPS in the lung of tumor-bearing mice with the concomitant progression of tumor cell proliferation.…”

Section: Discussionmentioning

confidence: 99%

“…pDCs can drive CD4 + T cells to become CD4 + CD25 + Foxp3 + cells, which are identified as Tregs (20,21). The role of Tregs in a tumor microenvironment can be translated into anergy and immunosuppression, favoring the immune escape of tumor cells with the concomitant increase of tumor burden (14,22). To evaluate whether pDCs were crucial for tumor outgrowth after LPS treatment, we depleted pDCs using a pDC depleting Ab (m927 Ab) (14,23).…”

Section: Low-dose Lps Facilitates An Immunosuppressive Environment Inmentioning

confidence: 99%

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Plasmacytoid Dendritic Cells Play a Key Role in Tumor Progression in Lipopolysaccharide-Stimulated Lung Tumor–Bearing Mice

Rega

Terlizzi

Luciano

et al. 2013

The Journal of Immunology

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The antitumor activity of LPS was first described by Dr. William Coley. However, its role in lung cancer remains unclear. The aim of our study was to elucidate the dose-dependent effects of LPS (0.1–10 μg/mouse) in a mouse model of B16-F10–induced metastatic lung cancer. Lung tumor growth increased at 3 and 7 d after the administration of low-dose LPS (0.1 μg/mouse) compared with control mice. This was associated with an influx of plasmacytoid dendritic cells (pDCs), regulatory T cells, myeloid-derived suppressor cells, and CD8+ regulatory T cells. In contrast, high-dose LPS (10 μg/mouse) reduced lung tumor burden and was associated with a greater influx of pDCs, as well as a stronger Th1 and Th17 polarization. Depletion of pDCs during low-dose LPS administration resulted in a decreased lung tumor burden. Depletion of pDCs during high-dose LPS treatment resulted in an increased tumor burden. The dichotomy in LPS effects was due to the phenotype of pDCs, which were immunosuppressive after the low-dose LPS, and Th1- and T cytotoxic–polarizing cells after the high-dose LPS. Adoptive transfer of T cells into nude mice demonstrated that CD8+ T cells were responsible for pDC recruitment following low-dose LPS administration, whereas CD4+ T cells were required for pDC influx after the high-dose LPS. In conclusion, our data suggest differential effects of low-dose versus high-dose LPS on pDC phenotype and tumor progression or regression in the lungs of mice.

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Section: Discussionmentioning

confidence: 99%

Section: Low-dose Lps Facilitates An Immunosuppressive Environment Inmentioning

confidence: 99%

Plasmacytoid Dendritic Cells Play a Key Role in Tumor Progression in Lipopolysaccharide-Stimulated Lung Tumor–Bearing Mice

Rega

Terlizzi

Luciano

et al. 2013

The Journal of Immunology

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“…This has been suggested recently based on vaccination studies using antigen formulated with a TLR-9 ligand, rendering conversion of Tregs into pre-activated T-helper cells that were then able to activate CD8 + CTLs [99]. In their model, reprogramming could be blocked by indoleamine 2,3-dioxygenase (IDO) derived from plasmocytoid DCs and activating Tregs [100,101] and restored by IDO inhibition. These results may also significantly impact mimotope vaccine design and open perspectives how to concretely interfere in future approaches with the immunosuppressive environment created by the tumor.…”

Section: The Principle Of Mimotope Vaccinesmentioning

confidence: 99%

Cancer vaccines inducing antibody production: more pros than cons

Jensen‐Jarolim¹,

Singer²

2011

Expert Review of Vaccines

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“…However, based on the well-known role of IDO in fetal immune privilege, it is clear that IDO is important for the function of the immune system. The expression of IDO by activated dendritic cells can serve to activate regulatory T cells (Tregs), thereby constituting one mechanism by which the immune system can restrict excessive lymphocyte reactivity (13). This mechanism has also been adopted by tumor cells to disable the immune system, permitting tumor progression.…”

Section: Introductionmentioning

confidence: 99%

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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Plasmacytoid dendritic cells from mouse tumor-draining lymph nodes directly activate mature Tregs via indoleamine 2,3-dioxygenase

Cited by 720 publications

References 54 publications

Plasmacytoid Dendritic Cells Play a Key Role in Tumor Progression in Lipopolysaccharide-Stimulated Lung Tumor–Bearing Mice

Plasmacytoid Dendritic Cells Play a Key Role in Tumor Progression in Lipopolysaccharide-Stimulated Lung Tumor–Bearing Mice

Cancer vaccines inducing antibody production: more pros than cons

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

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