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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The continually growing list of defined tumor antigens is broadening the potential applicability of tumor antigen-targeted cancer therapies. Although cancer vaccines and adoptive T-cell transfer have been shown to increase the frequency of circulating tumor antigen-specific T cells, these approaches cause clinical responses in a few patients. In melanoma, approximately one third of metastatic lesions contain activated T cells, including those specific for tumor antigens, arguing that the priming phase has occurred already in such individuals even without vaccination. These observations indicate that tumor resistance to immune destruction may dominate in many instances, arguing for a thorough analysis of the melanoma tumor microenvironment in individual patients. Recent work has suggested that T-cell anergy, the influence of CD4+ CD25+ regulatory T cells, the expression of inhibitory ligands, such as PD-L1, and the activity of nutrient-catabolizing enzymes, such as indoleamine 2,3-dioxygenase, may be involved. Preclinical murine models have shown that interfering with each of these processes can translate into T-cell-mediated tumor control. Importantly, each of these targets is amenable to clinical manipulation. Clinical translation of these approaches to counter negative regulation of antitumor immunity should receive high priority.
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PMID:Identifying and overcoming immune resistance mechanisms in the melanoma tumor microenvironment. 1660 53

The identification of tumor-expressed antigens that can be recognized by specific T lymphocytes has made it possible both to study the properties of T cells participating in anti-tumor immune responses in patients and also to develop antigen-specific immunotherapies as a treatment modality. Interestingly, moves toward intervention have proceeded at a faster pace than have investigations toward understanding. In melanoma in particular, many clinical trials of active immunization have been performed, and many of these have shown increases in tumor antigen-specific T cells circulating in the blood. However, clinical responses have been infrequent, arguing that mechanisms of resistance downstream from initial T cell priming may be dominant in many cases. In fact, may patients show spontaneous generation of immune effector cells and/or antibodies, implying that the priming phase has occurred already in such individuals even without vaccination. Recent attention has turned toward mechanisms of immune evasion at the effector phase of the anti-tumor immune response, predominantly within the tumor microenvironment. Evidence is accumulating that T cell-intrinsic hyporesponsiveness or anergy, extrinsic suppression by regulatory cell populations, inhibitory ligands such as PD-L1, soluble factors such as TGF-beta, and the activity of nutrient-catabolizing enzymes such as indoleamine 2,3-dioxygenase (IDO), may contribute to immune escape in different settings. Murine preclinical models have shown that interfering with each of these processes can translate into T cell-mediated tumor control. Clinical studies to estimate the frequency of specific immune evasion mechanisms in individual patients, to correlate specific events with clinical outcome, and to develop strategies to counter resistance mechanisms should receive a high priority.
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PMID:Immune suppression in the tumor microenvironment. 1669 66

Tumors evolve mechanisms to escape immune control by a process called immune editing, which provides a selective pressure in the tumor microenvironment that could lead to malignant progression. A variety of tumor-derived factors contribute to the emergence of complex local and regional immunosuppressive networks, including vascular endothelial growth factor, interleukin-10, transforming growth factor-beta, prostaglandin E(2), and soluble phosphatidylserine, soluble Fas, soluble Fas ligand, and soluble MHC class I-related chain A proteins. Although deposited at the primary tumor site, these secreted factors could extend immunosuppressive effects into the local lymph nodes and the spleen, promoting invasion and metastasis. Vascular endothelial growth factors play a key role in recruiting immature myeloid cells from the bone marrow to enrich the microenvironment as tumor-associated immature dendritic cells and tumor-associated macrophages. The understanding of the immunosuppressive networks that evolve is incomplete, but several features are emerging. Accumulation of tumor-associated immature dendritic cells may cause roving dendritic cells and T cells to become suppressed by the activation of indoleamine 2,3-dioxygenase and arginase I by tumor-derived growth factors. Soluble phosphatidylserines support tumor-associated macrophages by stimulating the release of anti-inflammatory mediators that block antitumor immune responses. Soluble Fas, soluble FasL, and soluble MHC class I-related chain A proteins may help tumor cells escape cytolysis by cytotoxic T cells and natural killer cells, possibly by counterattacking immune cells and causing their death. In summary, tumor-derived factors drive the evolution of an immunosuppressive network which ultimately extends immune evasion from the primary tumor site to peripheral sites in patients with cancer.
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PMID:Tumor-driven evolution of immunosuppressive networks during malignant progression. 1674 Jun 84

Hemangioma is a distinct category of benign vascular tumors characterized by presentation within the first weeks of life, rapid growth during the first year and variable degree of spontaneous involution over a period of several years. Recent research reported that CD8+ T cells in hemangiomas, and the endothelia of hemangioma uniquely expressed leukocyte marker FCgammaRII and myeloid cell marker. Presence of high levels of indoleamine 2,3-dioxygenase in proliferating hemangiomas and significantly decreasing during involution was also confirmed. Topical application of imiquimod cream, an immune regulator, to proliferating hemangiomas apparently accelerated regression of the lesions. These findings suggest immune response may be involved in the pathogenesis of hemangioma. The endothelia of hemangioma may express various markers to escape the immune surveillance. An immune response may be one of the mechanisms for hemangioma regression. Strategies with systemically or locally applying immune regulator into the tumor may be an applicable way in accelerating the involution of hemangioma.
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PMID:Immune response: A possible role in the pathophysiology of hemangioma. 1699 93

The extrahepatic enzyme indoleamine 2,3-dioxygenase (IDO) catalyzes tryptophan degradation in the first and rate-limiting step towards biosynthesis of the central metabolic co-factor nicotinamide adenine dinucleotide (NAD). While this pathway has been known for decades, the actual physiological role for IDO in mammals remained obscure, because (i.) most cell types do not express the downstream enzymes in the NAD biosynthesis pathway and (ii.) mammals salvage rather than synthesize NAD to meet their metabolic needs. An immunological role for IDO was hinted at with the observation that IDO expression is stimulated by interferon-gamma and subsequently confirmed by the discovery of its physiological importance in protecting the fetus from maternal immunity. Similarly, elevations in tryptophan catabolism in cancer patients were known since the 1950s, but the basis and meaning of this phenomenon were uncertain until it was shown that IDO, which is commonly elevated in tumors and draining lymph nodes, suppresses T cell immunity in the tumor microenvironment. Indeed, by creating peripheral tolerance to tumor antigens, IDO can undermine immune responses that thwart tumor cell survival in the context of an underlying inflammatory environment that facilitates tumor outgrowth. In preclinical studies, small molecule inhibitors of IDO compromise this mechanism of immunosuppression and strongly leverage the efficacy of a variety of classical chemotherapeutic agents, supporting the clinical development of IDO inhibitors as a therapeutic goal. This essay summarizes key findings that implicate IDO as an important mediator of peripheral tolerance and discusses the development of anti-cancer modalities that incorporate the use of IDO inhibitors.
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PMID:Indoleamine 2,3-dioxygenase in immune suppression and cancer. 1730 76

Foxp3(+) CD4(+)CD25(+) regulatory T (Treg) cells and immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO) play an important role in immunoregulation. Accumulating evidence shows that IDO and Treg cells have potent regulatory properties for immune escape in cancer. To evaluate the expression of IDO and the localization of Foxp3(+) Treg cells in the development and progression of uterine cervical cancer, IDO expression and Foxp3(+) Treg cells in the primary and metastatic lesions were studied using immunohistochemistry. IDO expression in tumor cells appeared in cervical intraepithelial neoplasia (CIN)-3 of the uterine cervix and marked expression in microinvasive cancer cells was observed. Interestingly, IDO expression in invasive cancer was confined to the cancer cells at the invasive front. Moreover, antigen-presenting cells (APC) at the invasive front in primary and metastatic lesions were also expressing IDO. Stromal Foxp3(+) Treg cells appeared in CIN-3 and increased in microinvasive and invasive cancer. Intraepithelial Foxp3(+) Treg cells were restricted within microinvasive and invasive cancer. No significant differences in the proportion of Foxp3(+)/CD4(+) in the stroma or epithelium, or between non-metastatic and metastatic invasive cancers, were observed in primary lesions of cervical cancer, while there was a significant increase (P < 0.005) in the proportion of Foxp3(+)/CD4(+) in metastatic lymph nodes compared with non-metastatic lymph nodes. Some of the Foxp3(+) Treg cells in metastatic lymph nodes contacted the IDO(+) APC. IDO expression at the invasive front of cancer cells and APC, and the localization of Foxp3(+) Treg cells in front of cancer tissues, may create a network between IDO and Treg for the induction of immune escape.
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PMID:Expression of indoleamine 2, 3-dioxygenase and the recruitment of Foxp3-expressing regulatory T cells in the development and progression of uterine cervical cancer. 1743 37

Amongst the numerous mediators contributing towards the escape of tumors from the host's immune response against them, the enzyme indoleamine 2,3-dioxygenase (IDO) has recently attracted special attention. By catabolizing tryptophan to N-formyl-kynurenine, IDO starves T cells from this important amino acid rendering them incapable of mounting appropriate immune responses. Originally, IDO has been associated to peripheral tolerance and maternal tolerance towards the fetus. The recent identification of IDO-expressing tumor cells has implicated this molecule as a key mediator of the tumor immune escape. Mounting evidence indicates that, within the tumor microenvironment, not only tumor cells but also other infiltrating cells such as dendritic cells, monocytes and others can be sources of IDO. IDO-induced tryptophan depletion from the tumor microenvironment could be the result of either elevated levels of the enzyme or augmented tryptophan consumption by both tumor cells and antigen presenting cells of the host. Beyond the tryptophan depletion, accumulation of its metabolites into the tumor environment seems to also propagate the suppression of anti-tumor immune responses. Finally, evidence emerges indicating that IDO possibly promotes tumor immune escape by inducing an immunoregulatory or an anergic T cell phenotype at a systemic level. In this context, anti-IDO therapeutic approaches are already under investigation, considering 1-methyl-tryptophan, its analogues as well as newly identified chemicals and natural extracts.
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PMID:Tumor immune escape mediated by indoleamine 2,3-dioxygenase. 1764 89

A small population of plasmacytoid DCs (pDCs) in mouse tumor-draining LNs can express the immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO). We show that these IDO+ pDCs directly activate resting CD4+CD25+Foxp3+ Tregs for potent suppressor activity. In vivo, Tregs isolated from tumor-draining LNs were constitutively activated and suppressed antigen-specific T cells immediately ex vivo. In vitro, IDO+ pDCs from tumor-draining LNs rapidly activated resting Tregs from non-tumor-bearing hosts without the need for mitogen or exogenous anti-CD3 crosslinking. Treg activation by IDO+ pDCs was MHC restricted, required an intact amino acid-responsive GCN2 pathway in the Tregs, and was prevented by CTLA4 blockade. Tregs activated by IDO markedly upregulated programmed cell death 1 ligand 1 (PD-L1) and PD-L2 expression on target DCs, and the ability of Tregs to suppress target T cell proliferation was abrogated by antibodies against the programmed cell death 1/PD-L (PD-1/PD-L) pathway. In contrast, Tregs activated by anti-CD3 crosslinking did not cause upregulation of PD-Ls, and suppression by these cells was unaffected by blocking the PD-1/PD-L pathway. Tregs isolated from tumor-draining LNs in vivo showed potent PD-1/PD-L-mediated suppression, which was selectively lost when tumors were grown in IDO-deficient hosts. We hypothesize that IDO+ pDCs create a profoundly suppressive microenvironment within tumor-draining LNs via constitutive activation of Tregs.
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PMID:Plasmacytoid dendritic cells from mouse tumor-draining lymph nodes directly activate mature Tregs via indoleamine 2,3-dioxygenase. 1771 Feb 30

The enzyme indoleamine 2,3-dioxygenase (IDO) catalyzes degradation of tryptophan, an essential amino acid required for lymphocyte activation and proliferation. Many tumors express IDO which implies that it acts as a mechanism to evade T cell-mediated immune attack, and also to establish an immunosuppressive tumor microenvironment. The purpose of this study was to determine whether primary and metastatic uveal melanoma expressed the IDO gene and whether uveal melanoma cells could deplete tryptophan. In situ expression of IDO in primary uveal melanoma from tumor bearing eyes and metastatic uveal melanoma liver tissues was determined by immunohistostaining with IDO-specific antibody. Reverse transcription PCR was used to assess IDO gene transcription by primary and metastatic uveal melanoma cell lines. IDO protein expression was determined by Western blot of uveal melanoma cell protein lysate. IDO catalytic activity was assessed by measuring the presence of kynurenine, a product generated by tryptophan degradation, in uveal melanoma culture supernatants. Primary uveal melanoma from tumor-bearing eyes and metastatic uveal melanoma from the liver did not express IDO in situ. IDO was not constitutively expressed in either primary or metastatic uveal melanoma cell lines. However, stimulation of primary and metastatic uveal melanoma cell cultures with interferon-gamma (IFN-gamma) universally upregulated both IDO gene and protein expression. Culture supernatants from IFN-gamma treated primary and metastatic uveal melanoma cell cultures contained elevated levels of kynurenine. Addition of the IDO inhibitor 1-methyl dl-tryptophan significantly diminished kynurenine levels in IFN-gamma treated uveal melanoma cell cultures. The results from this study suggest that IFN-gamma inducible IDO upregulation by primary and metastatic uveal melanoma may generate a local immune privileged microenvironment to promote escape from T cell-mediated immune surveillance.
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PMID:Uveal melanoma expression of indoleamine 2,3-deoxygenase: establishment of an immune privileged environment by tryptophan depletion. 1787 68

The clinical investigation of numerous therapeutic cancer vaccine strategies has resulted in relative disappointment. Whereas a minority of patients have indeed experienced clinical benefit, the majority of patients show disease progression even in cases in which induction of functional tumor antigen-specific T-cell responses as measured in the blood is easily detected. This observation has led to interrogation of the tumor microenvironment for potential mechanisms of tumor resistance to the effector phase of the antitumor T-cell response. Poor chemokine-mediated trafficking of effector cells and the action of negative regulatory pathways that inhibit T-cell function have been identified as key limiting factors. Important negative regulatory pathways include T-cell anergy from insufficient B7 costimulation, extrinsic suppression by regulatory T-cell populations, direct inhibition through inhibitory ligands such as PD-L1, and metabolic dysregulation such as through the activity of indoleamine 2,3-dioxygenase. Recognition of these evasion mechanisms has pointed toward new therapeutic approaches for cancer immunotherapy.
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PMID:Failure at the effector phase: immune barriers at the level of the melanoma tumor microenvironment. 1787 53


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