Indoleamine 2,3-Dioxygenase 1 (IDO1) Is Up-Regulated in Thyroid Carcinoma and Drives the Development of an Immunosuppressant Tumor Microenvironment

Moretti, Sonia; Menicali, Elisa; Voce, Pasquale; Morelli, Silvia; Cantarelli, Sara; Sponziello, Marialuisa; Colella, Renato; Fallarino, Francesca; Orabona, Ciriana; Alunno, Alessia; Biase, Dario de; Bini, Vittorio; Mameli, Maria Grazia; Filetti, Sébastiano; Gerli, Roberto; Macchiarulo, Antonio; Melillo, Rosa Marina; Tallini, Giovanni; Santoro, Massimo; Puccetti, Paolo; Avenia, Nicola; Puxeddu, Efisio

doi:10.1210/jc.2013-3351

Cited by 74 publications

(69 citation statements)

References 35 publications

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“…However, when an inhibitor of the the indoleamine 2,3-dioxygenase (IDO) enzyme (1-methyltriptophan) was given together with the RET peptide (Zeng et al 2009), effective anti-tumor immunity was elicited. Interestingly, IDO expression can be increased by activated RET in a STAT1-dependent manner (Moretti et al 2014). These data confirm that RET induces the expression of immunosuppressive molecules and that anti-cancer immunity can be elicited only when these molecules are blocked.…”

Section: Ret and Cancer Immunotherapy In Men2supporting

confidence: 59%

RET-mediated modulation of tumor microenvironment and immune response in multiple endocrine neoplasia type 2 (MEN2)

Castellone¹,

Melillo²

2018

Endocrine-Related Cancer

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Medullary thyroid carcinomas (MTC) arise from thyroid parafollicular, calcitoninproducing C-cells and can occur either as sporadic or as hereditary diseases in the context of familial syndromes, including multiple endocrine neoplasia 2A (MEN2A), multiple endocrine neoplasia 2B (MEN2B) and familial MTC (FMTC). In a large fraction of sporadic cases, and virtually in all inherited cases of MTC, activating point mutations of the RET proto-oncogene are found. RET encodes for a receptor tyrosine kinase protein endowed with transforming potential on thyroid parafollicular cells. As in other cancer types, microenvironmental factors play a critical role in MTC. Tumor-associated extracellular matrix, stromal cells and immune cells interact and influence the behavior of cancer cells both in a tumor-promoting and in a tumor-suppressing manner. Several studies have shown that, besides the neoplastic transformation of thyroid C-cells, a profound modification of tumor microenvironment has been associated to the RET FMTC/MEN2-associated oncoproteins. They influence the surrounding stroma, activating cancerassociated fibroblasts (CAFs), promoting cancer-associated inflammation and suppressing anti-cancer immune response. These mechanisms might be exploited to develop innovative anti-cancer therapies and novel prognostic tools in the context of familial, RET-associated MTC.

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Section: Ret and Cancer Immunotherapy In Men2supporting

confidence: 59%

RET-mediated modulation of tumor microenvironment and immune response in multiple endocrine neoplasia type 2 (MEN2)

Castellone¹,

Melillo²

2018

Endocrine-Related Cancer

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“…Recently, studies have shown that the BRAF V600E protein mutation is associated with immunosuppressive mechanisms in PTC, such as indoleamine 2,3-dioxygenase 1 (IDO) (23), human leukocyte antigen G (HLA-G) (24), and programmed death ligand 1 (PD-L1) expression (25). Studies of TIL in other cancer types have shown that specific patterns predict cancer behavior, such as the correlation between a low CD8 + effector T cell to FoxP3 + suppressor T cell ratio with greater tumor aggressiveness and worse patient outcomes (17,(19)(20)(21).…”

Section: Introductionmentioning

confidence: 99%

BRAF^V600E in Papillary Thyroid Carcinoma Is Associated with Increased Programmed Death Ligand 1 Expression and Suppressive Immune Cell Infiltration

Angell

Lechner

Jang

et al. 2014

Thyroid

116

102

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Background: There remain a small number of patients with papillary thyroid cancer (PTC) who suffer recurrence, metastases, or death. While mutation of the BRAF gene, corresponding to the constitutively active BRAF V600E protein, has been associated with worse clinical outcomes in thyroid cancer, the reasons underlying this observation are presently unknown. Disruption of endogenous host immune surveillance and promotion of tumor immune escape is one mechanism by which BRAF V600E tumors may achieve more aggressive behavior. This study evaluated the relationship between BRAF V600E status and known strategies of tumor-mediated immune suppression. Methods: Tissue sections of PTC tumors from 33 patients were evaluated by immunohistochemistry for tumorexpressed suppressive ligands and enzymes and effector and suppressor populations of tumor-infiltrating immune cells. Presence of BRAF V600E was evaluated by direct DNA sequencing of PTC specimens and the results correlated with tumor-expressed molecules and tumor-infiltrating immune cell populations, as well as patient characteristics and pathologic findings. Results: BRAF V600E tumors more often express high levels of immunosuppressive ligands programmed death ligand 1 (53% vs. 12.5%) and human leukocyte antigen G (41% vs. 12.5%) compared to BRAF wild-type tumors. There was no association between indoleamine 2,3-dioxygenase 1 expression and BRAF V600E status. Furthermore, BRAF V600E tumors demonstrate both lower CD8 + effector to FoxP3 + regulatory T cell, and CD68 + pan-macrophage to CD163 + M2 macrophage ratios, indicating relative increases in suppressive T cell and macrophage components, respectively. Conclusions: Overall, BRAF V600E PTC tumors display a broadly immunosuppressive profile and evidence of disturbed host tumor immune surveillance that may contribute to the poorer outcomes observed in this subset of patients with thyroid cancer.

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“…Cultured mouse peritoneal Mac1 + macrophages (E) and splenic CD11c + dendritic cells (F) strongly expressed IDO upon stimulation with interferon gamma. (30,31), a neoplasia long known to be associated with a prominent lymphocytic infiltration (32). Several drugs are therefore being developed to decrease the levels of IDO (and thus increase the extracellular concentration of tryptophan) as a way to boost the activity of tumor-specific effector T cells (33).…”

Section: Discussionmentioning

confidence: 99%

Exacerbation of Autoimmune Thyroiditis by CTLA-4 Blockade: A Role for IFNγ-Induced Indoleamine 2, 3-Dioxygenase

Sharma

Dalmazi

Caturegli

2016

Thyroid

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Background: Cytotoxic T-lymphocyte associated protein 4 (CTLA-4) is a negative regulator of immune responses that suppresses the activity of effector T cells and contributes to the maintenance of self tolerance. When blocked therapeutically, CTLA-4 leads to an overall activation of T cells that has been exploited for cancer control, a control associated however with a variety of immune-related side effects such as autoimmune thyroiditis. To investigate the mechanism(s) underlying this form of thyroiditis, we used the NOD-H2h4 mouse, a model that develops thyroiditis at very high incidence after addition of iodine to the drinking water. Methods: NOD-H2 h4 mice were started on drinking water supplemented with 0.05% sodium iodide when 8 weeks old and then injected with a hamster monoclonal antibody against mouse CTLA-4, polyclonal hamster immunoglobulins, or phosphate buffered saline when 11 weeks old. One month later (15 weeks of age), mice were sacrificed to assess thyroiditis, general immune responses in blood and spleen, and expression of indoleamine 2, 3-dioxygenase (IDO) in the thyroid and in isolated antigen-presenting cells after stimulation with interferon gamma. The study also analyzed IDO expression in four autopsy cases of metastatic melanoma who had received treatment with a CTLA-4 blocking antibody, and six surgical pathology Hashimoto thyroiditis controls. Results: CTLA-4 blockade worsened autoimmune thyroiditis, as assessed by a greater incidence, a more aggressive mononuclear cell infiltration in thyroids, and higher thyroglobulin antibody levels when compared to the control groups. CTLA-4 blockade also expanded the proportion of splenic CD4+ effector T cells, as well as the production of interleukin (IL)-2, interferon gamma, IL-10, and IL-13 cytokines. Interestingly, CTLA-4 blockade induced a strong expression of IDO in mouse and human thyroid glands, an expression that could represent a counter-regulatory mechanism to protect against the inflammatory environment. Conclusions: This study shows that CTLA-4 blockade exacerbates the iodine-accelerated form of thyroiditis typical of the NOD-H2 h4 mouse. The study could also have implications for cancer patients who develop thyroiditis as an immune-related adverse event after CTLA-4 blockade.

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Indoleamine 2,3-Dioxygenase 1 (IDO1) Is Up-Regulated in Thyroid Carcinoma and Drives the Development of an Immunosuppressant Tumor Microenvironment

Abstract: For the first time, this study demonstrates a pivotal role of IDO1 in the suppression of lymphocyte function in thyroid carcinoma microenvironment.

Cited by 74 publications

References 35 publications

RET-mediated modulation of tumor microenvironment and immune response in multiple endocrine neoplasia type 2 (MEN2)

RET-mediated modulation of tumor microenvironment and immune response in multiple endocrine neoplasia type 2 (MEN2)

BRAF^V600E in Papillary Thyroid Carcinoma Is Associated with Increased Programmed Death Ligand 1 Expression and Suppressive Immune Cell Infiltration

Exacerbation of Autoimmune Thyroiditis by CTLA-4 Blockade: A Role for IFNγ-Induced Indoleamine 2, 3-Dioxygenase

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Indoleamine 2,3-Dioxygenase 1 (IDO1) Is Up-Regulated in Thyroid Carcinoma and Drives the Development of an Immunosuppressant Tumor Microenvironment

Abstract: For the first time, this study demonstrates a pivotal role of IDO1 in the suppression of lymphocyte function in thyroid carcinoma microenvironment.

Cited by 74 publications

References 35 publications

RET-mediated modulation of tumor microenvironment and immune response in multiple endocrine neoplasia type 2 (MEN2)

RET-mediated modulation of tumor microenvironment and immune response in multiple endocrine neoplasia type 2 (MEN2)

BRAFV600E in Papillary Thyroid Carcinoma Is Associated with Increased Programmed Death Ligand 1 Expression and Suppressive Immune Cell Infiltration

Exacerbation of Autoimmune Thyroiditis by CTLA-4 Blockade: A Role for IFNγ-Induced Indoleamine 2, 3-Dioxygenase

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BRAF^V600E in Papillary Thyroid Carcinoma Is Associated with Increased Programmed Death Ligand 1 Expression and Suppressive Immune Cell Infiltration