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

T lymphocytes represent the main effectors of the immune response that can lead to tumor rejection, which represents the aim of various approaches of immunotherapy that are currently tested. However, in many cases, tumor cells appear to resist immune rejection. We have recently uncovered a new mechanism of tumoral immune resistance based on the expression by tumor cells of indoleamine 2,3-dioxygenase (IDO), an enzyme that rapidly degrades tryptophan, an amino acid that is crucial to sustain proliferation of T lymphocytes. We showed that most human tumors constitutively express IDO. We also observed that expression of IDO by immunogenic mouse tumor cells, prevents their rejection by pre-immunized mice. This effect is accompanied by a lack of accumulation of specific T cells at the tumor site, and can be partly reverted by systemic treatment of mice with an inhibitor of IDO, in the absence of noticeable toxicity. These results suggest that the efficacy of therapeutic vaccination of cancer patients might be improved by concomitant administration of an IDO inhibitor.
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PMID:[A new mechanism of tumor resistance to the immune system, based on tryptophan breakdown by indoleamine 2,3-dioxygenase]. 1513 6

Expression of indoleamine 2,3-dioxygenase (IDO) in epithelium of the endometrium and the cervix is not restricted to normal but also present in carcinomatous tissue. The enzyme was found in the majority of cases studied, pioneer cells at the invasion front of the tumors being especially strongly reactive in immunohistology. In addition, also cells in the peritumoral infiltrate of the stroma expressed IDO. Taken together, these findings together with previous data on the immunosuppressive impact of tryptophan depletion suggest IDO-induced suppression of antitumoral immune response in both adenocarcinoma and squamous cell carcinoma of endometrium and cervix. On the other hand, IDO as also known to inhibit tumor cell proliferation by tryptophan depletion.
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PMID:Expression of indoleamine 2,3-dioxygenase in carcinoma of human endometrium and uterine cervix. 1520 20

One mechanism contributing to immunologic unresponsiveness toward tumors may be presentation of tumor antigens by tolerogenic host APCs. We show that mouse tumor-draining LNs (TDLNs) contained a subset of plasmacytoid DCs (pDCs) that constitutively expressed immunosuppressive levels of the enzyme indoleamine 2,3-dioxygenase (IDO). Despite comprising only 0.5% of LN cells, these pDCs in vitro potently suppressed T cell responses to antigens presented by the pDCs themselves and also, in a dominant fashion, suppressed T cell responses to third-party antigens presented by nonsuppressive APCs. Adoptive transfer of DCs from TDLNs into naive hosts created profound local T cell anergy, specifically toward antigens expressed by the transferred DCs. Anergy was prevented by targeted disruption of the IDO gene in the DCs or by administration of the IDO inhibitor drug 1-methyl-D-tryptophan to recipient mice. Within the population of pDCs, the majority of the functional IDO-mediated suppressor activity segregated with a novel subset of pDCs coexpressing the B-lineage marker CD19. We hypothesize that IDO-mediated suppression by pDCs in TDLNs creates a local microenvironment that is potently suppressive of host antitumor T cell responses.
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PMID:Expression of indoleamine 2,3-dioxygenase by plasmacytoid dendritic cells in tumor-draining lymph nodes. 1525 95

The specificity of antitumor immunity continues to attract interest as a potentially powerful mode of cancer treatment. Cancer vaccines and adoptive T-cell infusion are strategies that can increase the frequency of circulating tumor antigen-specific T-cells. However, although these approaches can produce clinical responses in a minority of patients, tumor escape from immune destruction appears to dominate in many instances. Several molecular mediators of tumor resistance to immune effector cells have been identified that can be targeted pharmacologically. Two of these, the tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase and the T-cell inhibitory programmed death ligand 1, are discussed in this review. Blockade of these molecules may increase the efficacy of tumor-specific T-cell therapies in cancer patients.
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PMID:Overcoming immune resistance in the tumor microenvironment by blockade of indoleamine 2,3-dioxygenase and programmed death ligand 1. 1564 49

Immune escape is a crucial feature of cancer progression about which little is known. Elevation of the immunomodulatory enzyme indoleamine 2,3-dioxygenase (IDO) in tumor cells can facilitate immune escape. Not known is how IDO becomes elevated or whether IDO inhibitors will be useful for cancer treatment. Here we show that IDO is under genetic control of Bin1, which is attenuated in many human malignancies. Mouse knockout studies indicate that Bin1 loss elevates the STAT1- and NF-kappaB-dependent expression of IDO, driving escape of oncogenically transformed cells from T cell-dependent antitumor immunity. In MMTV-Neu mice, an established breast cancer model, we show that small-molecule inhibitors of IDO cooperate with cytotoxic agents to elicit regression of established tumors refractory to single-agent therapy. Our findings suggest that Bin1 loss promotes immune escape in cancer by deregulating IDO and that IDO inhibitors may improve responses to cancer chemotherapy.
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PMID:Inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1, potentiates cancer chemotherapy. 1571 57

By mediating tryptophan catabolism, the enzyme indoleamine 2,3-dioxygenase (IDO) has a complex role in immunoregulation in infection, pregnancy, autoimmunity, transplantation, and neoplasia. We hypothesized that IDO might affect the outcome of the infection in mice infected with Candida albicans by virtue of its potent regulatory effects on inflammatory and T cell responses. IDO expression was examined in mice challenged with the fungus along with the consequences of its blockade by in vivo treatment with an enzyme inhibitor. We found that IDO activity was induced at sites of infection as well as in dendritic cells and effector neutrophils via IFN-gamma- and CTLA-4-dependent mechanisms. IDO inhibition greatly exacerbated infection and associated inflammatory pathology as a result of deregulated innate and adaptive/regulatory immune responses. However, a role for tryptophan catabolism was also demonstrated in a fungus-autonomous fashion; its blockade in vitro promoted yeast-to-hyphal transition. These results provide novel mechanistic insights into complex events that, occurring at the fungus/pathogen interface, relate to the dynamics of host adaptation to the fungus. The production of IFN-gamma may be squarely placed at this interface, where IDO activation probably exerts a fine control over fungal morphology as well as inflammatory and adaptive antifungal responses.
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PMID:A crucial role for tryptophan catabolism at the host/Candida albicans interface. 1572 2

We evaluated the clinical significance of indoleamine 2,3-dioxygenase (IDO) in breast cancer. Operative specimens obtained from 30 patients with breast cancer were investigated by semiquantitative RT-PCR with specific primers against IDO. The correlations among IDO expression, clinicopathologic factors and prognosis were studied. The expression of IDO was observed in 100%, both of the cancer specimens and the non-cancer specimens. The IDO expression of the cancer specimens was higher than the non-cancer specimens. The expression of IDO did not correlate to histologic classification, tumor size, lymphatic invasion, venous invasion and lymph nodes metastasis, but correlated to clinical stage and the serum level of immunosuppressive acidic protein (IAP). There were no correlations for a survival rate after surgery between the high IDO level group and the one. The serum IDO levels of cancer patients were higher than that of a healthy volunteer measured by semiquantitative RT-PCR and HPLC. It is suggested that the expression of IDO in breast cancer patients may play a critical role for immunosuppression in those patients.
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PMID:[Study of indoleamine 2,3-dioxygenase expression in patients with breast cancer]. 1631 64

Production of indoleamine 2,3-dioxygenase (IDO) by tumor cells, leading to tryptophan depletion and production of immunosuppressive metabolites, may facilitate immune tolerance of cancer. IDO gene is also expressed in dendritic cells (DC) upon maturation induced by lipopolysaccarides or IFN. We investigated IDO gene expression in melanoma cell lines and clinical specimens as compared to mature DC (mDC). Furthermore, we explored effects of L-kynurenine (L-kyn) and 3-hydroxyanthranilic acid (3-HAA) on survival and antigen-dependent and independent proliferation of CD8(+) cells. We observed that IDO gene expression in cultured tumor cells and freshly excised samples is orders of magnitude lower than in mDC, providing highly efficient antigen presentation to CD8(+) T cells. Non toxic concentrations of L-kyn or 3-HAA did not significantly inhibit antigen-specific CTL responses. However, 3-HAA, but not L-kyn markedly inhibited antigen-independent proliferation of CD8(+) T cells induced by common receptor gamma-chain cytokines IL-2, -7 and -15. Our data suggest that CD8(+) T cell activation induced by antigenic stimulation, a function exquisitely fulfilled by mDC, is unaffected by tryptophan metabolites. Instead, in the absence of effective T cell receptor triggering, 3-HAA profoundly affects homeostatic proliferation of CD8(+) T cells.
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PMID:Differential effects of the tryptophan metabolite 3-hydroxyanthranilic acid on the proliferation of human CD8+ T cells induced by TCR triggering or homeostatic cytokines. 1638 30

Tumors create an abnormal state of tolerance toward themselves and their antigens. One mechanism that might contribute to this tolerance is the immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO). IDO-expressing antigen-presenting cells are found in tumor-draining lymph nodes, where they can create a tolerogenic microenvironment. IDO can also be expressed within the tumor itself, by tumor cells or host stromal cells, where it can inhibit the effector phase the immune response. Finally, emerging evidence suggests that IDO might also constitute a significant counter-regulatory mechanism, induced by clinically relevant pro-inflammatory signals, such as IFN-gamma, IFN-alpha, CpG oligodeoxynucleotides, and 4-1BB ligation. Strategies to inhibit the IDO pathway may thus assist in breaking tolerance to tumors, and might enhance the efficacy of other immunotherapy strategies by removing unwanted counter-regulation.
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PMID:Indoleamine 2,3-dioxygenase, tumor-induced tolerance and counter-regulation. 1646 Sep 21

Immune tolerance is a central mechanism counteracting tumor-specific immunity and preventing effective anticancer immunotherapy. Induction of tolerance requires a specific environment in which tolerogenic dendritic cells (DCs) play an essential role deviating the immune response away from effective immunity. It was recently shown that maturation of DCs in the presence of PGE2 results in upregulation of indoleamine 2,3-dioxygenase (IDO) providing a potential mechanism for the development of DC-mediated Tcell tolerance. Here, we extend these findings, demonstrating a concomitant induction of IDO and secretion of soluble CD25 after DC maturation in the presence of PGE2. While maturation of DCs induced IDO expression on transcriptional level, only integration of PGE2 signaling led to up-regulation of functional IDO protein as well as significant expression of cell-surface and soluble CD25 protein. As a consequence, T-cell proliferation and cytokine production were significantly inhibited, which was mediated mainly by IDO-induced tryptophan depletion. Of importance, we demonstrate that different carcinoma entities associated with elevated levels of PGE2 coexpress CD25 and IDO in peritumoral dendritic cells, suggesting that PGE2 might influence IDO expression in human DCs in the tumor environment. We therefore suggest PGE2 to be a mediator of early events during induction of immune tolerance in cancer.
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PMID:CD25 and indoleamine 2,3-dioxygenase are up-regulated by prostaglandin E2 and expressed by tumor-associated dendritic cells in vivo: additional mechanisms of T-cell inhibition. 1652 17


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