Reinstalling Antitumor Immunity by Inhibiting Tumor-Derived Immunosuppressive Molecule IDO through RNA Interference

Zheng, Xiufen; Koropatnick, James; Li, Mu; Zhang, Xusheng; Ling, Fengjun; Ren, Xiubao; Hao, Xishan; Sun, Hongtao; Vladau, Costin; Franék, J; Feng, Biao; Urquhart, Bradley L.; Zhong, Robert; Freeman, David J.; García, Bertha; Wei, Min

doi:10.4049/jimmunol.177.8.5639

Cited by 94 publications

(83 citation statements)

References 41 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: 84%

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: 84%

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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“…IDOexpressing dendritic cells suppress allogeneic T cell proliferation in vitro by tryptophan metabolites (7) and IDO action attenuates allograft injury or rejection (12)(13)(14). Tryptophan catabolism also induces regulatory cells and is a means by which CTLA-4 signaling functions in vivo (15)(16)(17) while inhibiting IDO restores antitumor immunity (18). Hence, IDO-mediated tryptophan catabolism plays a key role in the maintenance of immunologic tolerance.…”

Section: Suppression Of Memory Cd8 T Cell Generation Andmentioning

confidence: 99%

Suppression of Memory CD8 T Cell Generation and Function by Tryptophan Catabolism

Liu

Dai

et al. 2007

The Journal of Immunology

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Dendritic cell-derived indoleamine 2,3-dioxygenase (IDO) suppresses naive T cell proliferation and induces their apoptosis by catalyzing tryptophan, and hence is essential for the maintenance of peripheral tolerance. However, it is not known whether memory T cells are subject to the regulation by IDO-mediated tryptophan catabolism, as memory T cells respond more rapidly and vigorously than their naive counterparts and are resistant to conventional costimulatory blockade. In this study, we present the evidence that memory CD8+ T cells are susceptible to tryptophan catabolism mediated by IDO. We found that overexpression of IDO in vivo attenuated the generation of both central memory CD8+ T cells (TCM) and effector memory CD8+ T cells (TEM) while suppressing IDO activity promoted their generation. Moreover, IDO overexpression suppressed the effector function of TCM cells or TCM cell-mediated allograft rejection as well as their proliferation in vivo. Interestingly, TCM cells were resistant to apoptosis induced by tryptophan catabolism. However, IDO overexpression did not suppress the effector function of TEM cells or TEM cell-mediated allograft rejection, suggesting that TEM cells, unlike TCM cells, do not require tryptophan for their effector function once they are generated. This study provides insight into the mechanisms underlying the differential regulation of memory T cell responsiveness and has clinical implications for vaccination or tolerance induction.

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“…It is upregulated by IFN-g and causes tryptophan breakdown, which leads to T-cell apoptosis (Lob et al, 2009). Interventions aimed at silencing IDO expression have shown anti-tumour activity in a mouse melanoma model (Zheng et al, 2006).…”

Section: Suppression By Regulatory T Cellsmentioning

confidence: 99%

Harnessing the immune response to treat cancer

et al. 2010

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It is well established that the immune system has the capacity to attack malignant cells. During malignant transformation cells acquire numerous molecular and biochemical changes that render them potentially vulnerable to immune cells. Yet it is self-evident that a growing tumour has managed to evade these host defence mechanisms. The exact ways in which the immune system interacts with tumour cells and how cancers are able to escape immunological eradication have only recently started to be fully elucidated. Understanding the relationship between the tumour and the anti-tumour immune response and how this can be altered with conventional treatments and immune-targeted therapies is crucial to developing new treatments for patients with cancer. In this review, focusing on the anti-tumour T-cell response, we summarize our understanding of how tumours, cancer treatments and the immune system interact, how tumours evade the immune response and how this process could be manipulated for the benefit of patients with cancer.

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Reinstalling Antitumor Immunity by Inhibiting Tumor-Derived Immunosuppressive Molecule IDO through RNA Interference

Cited by 94 publications

References 41 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

Suppression of Memory CD8 T Cell Generation and Function by Tryptophan Catabolism

Harnessing the immune response to treat cancer

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