Indoleamine 2,3-dioxygenase Affects the Aggressiveness of Intraductal Papillary Mucinous Neoplasms Through Foxp3+CD4+CD25+ T Cells in Peripheral Blood

Ikemoto, Tetsuya; Shimada, Mitsuo; Komatsu, Masato; Yamada, Shinichiro; Saito, Yu; Mori, Hiroki; Morine, Yuji; Imura, Satoru; Bando, Yoshimi; Utsunomiya, Tohru

doi:10.1097/mpa.0b013e3182575e4a

Cited by 16 publications

(13 citation statements)

References 15 publications

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“…Therefore, we hypothesized a certain molecule which was induced by IFN-γ in non CD4+ cells suppressed the production of IL-17 of CD4+ T cells. IDO was one of the candidate molecules as it was induced by IFN-γ [25] in non CD4+ cells and known to be associated with Treg [26]–[29] which suppresses Th17. Pretreatment of 1-MT partially restored the production of IL-17 suppressed by IFN-γ (Figure 4b).…”

Section: Resultsmentioning

confidence: 99%

Interferon Gamma Suppresses Collagen-Induced Arthritis by Regulation of Th17 through the Induction of Indoleamine-2,3-Deoxygenase

Lee

Park

et al. 2013

PLoS ONE

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C57BL/6 mice are known to be resistant to the development of collagen-induced arthritis (CIA). However, they show a severe arthritic phenotype when the Ifng gene is deleted. Although it has been proposed that IFN-γ suppresses inflammation in CIA via suppressing Th17 which is involved in the pathogenesis of CIA, the exact molecular mechanism of the Th17 regulation by IFN-γ is poorly understood. This study was conducted to 1) clarify that arthritogenic condition of IFN-γ knockout (KO) mice is dependent on the disinhibition of Th17 and 2) demonstrate that IFN-γ-induced indoleamine2,3dioxgenase (IDO) is engaged in the regulation of Th17. The results showed that the IFN-γ KO mice displayed increased levels of IL-17 producing T cells and the exacerbation of arthritis. Also, production of IL-17 by the splenocytes of the IFN-γ KO mice was increased when cultured with type II collagen. When Il17 was deleted from the IFN-γ KO mice, only mild arthritis developed without any progression of the arthritis score. The proportion of CD44highCD62Llow memory-like T cells were elevated in the spleen, draining lymph node and mesenteric lymph node of IFN-γ KO CIA mice. Meanwhile, CD44lowCD62Lhigh naïve T cells were increased in IFN-γ and IL-17 double KO CIA mice. When Th17 polarized CD4+ T cells of IFN-γ KO mice were co-cultured with their own antigen presenting cells (APCs), a greater increase in IL-17 production was observed than in co-culture of the cells from wild type mice. In contrast, when APCs from IFN-γ KO mice were pretreated with IFN-γ, there was a significant reduction in IL-17 in the co-culture system. Of note, pretreatment of 1-methyl-DL- tryptophan, a specific inhibitor of IDO, abolished the inhibitory effects of IFN-γ. Given that IFN-γ is a potent inducer of IDO in APCs, these results suggest that IDO is involved in the regulation of IL-17 by IFN-γ.

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Section: Resultsmentioning

confidence: 99%

Interferon Gamma Suppresses Collagen-Induced Arthritis by Regulation of Th17 through the Induction of Indoleamine-2,3-Deoxygenase

Lee

Park

et al. 2013

PLoS ONE

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“…We previously showed that Foxp3 + Treg populations in peripheral blood can reflect the pathological aggressiveness of pancreatic ductal carcinomas and IPMNs (4,12). The numbers of Foxp3 + T cells were found to be increased in immune cells infiltrating pancreatic cancers and in draining lymph nodes (7,22), however, the mechanism by which Foxp3+Treg populations are expanded in peripheral blood from the tumor environment remained unclear (23).…”

Section: Discussionmentioning

confidence: 99%

“…IDO is a critical enzyme for maintaining pregnancy (9) and plays an important role in tumor immunity (10,11). An investigation of the associations of IDO with IPMN aggressiveness and Treg immunity showed that Treg increases induced by IDO + DCs are associated with peritumoral lesions (12). However, the mechanism underlying the expansion of Tregs in peripheral blood, as well as in the peritumoral environment, remains unclear.…”

mentioning

confidence: 99%

Peripheral Tr1 and Foxp3+ Treg as Markers of Recurrent Malignancies in Patients with Hepato-Biliary Pancreatic Cancers

Ikemoto

Shimada

Ishikawa

et al. 2017

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Abstract. Background Foxp3 + regulatory T cells (Foxp3 + Tregs) play an important role in tumor immunity (1-3). Populations of peripheral Foxp3 + Tregs were found to be greater in pancreatic cancer patients than in healthy controls, with peripheral Foxp3 + Treg populations strongly correlating with TMN classifications (4). In addition, peripheral Foxp3 + Treg populations were found to significantly correlate with the pathological aggressiveness of intraductal papillary mucinous neoplasms (IPMNs), a correlation dependent on Notch signaling (5). Although Treg populations have been reported to be higher in peritumoral lesions and in draining lymph nodes, the precise mechanism underlying the increase in peripheral Tregs in cancer patients has not been determined (6, 7).Treg expansion following organ transplantation has been reported to depend on indoleamine 2, 3-dioxygenase (IDO) activity of dendritic cells (DCs) (8). IDO is a critical enzyme for maintaining pregnancy (9) and plays an important role in tumor immunity (10,11). An investigation of the associations of IDO with IPMN aggressiveness and Treg immunity showed that Treg increases induced by IDO + DCs are associated with peritumoral lesions (12). However, the mechanism underlying the expansion of Tregs in peripheral blood, as well as in the peritumoral environment, remains unclear. Tregs are easily influenced by other factors that alter host immunology, such as infection and chemo/radiation therapy, suggesting the need for more precise and stable immunological parameters to evaluate tumor immunity, especially after surgery.CD4 + CD49b + LAG3 + regulatory T cells (type 1 regulatory T cells, or Tr1s) were recently reported to have strong regulatory activities in autoimmune diseases (13). Tr1s were originally found in the peripheral blood of patients with severe combined immunodeficiency and long-term mixed chimerism after human leukocyte antigen (HLA)-mismatched fetal liver hematopoietic stem cell transplantation (14). The primary 5541

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“…IDO-positive cells in IPMNs can induce an increase in the FOXP3+ cells. [51] Natural Killer (NK) cells are key components in the innate immune system and are capable of destroying the cancer cells directly. Dysfunction of NK cells has been investigated in pancreatic cancer.…”

Section: Ido In Prostate Cancermentioning

confidence: 99%

“…IDO is involved in immune system regulation. IDO upregulation is associated with poor prognosis in various cancers [20,30,34,35,39,41,43,51] but few studies suggested that increased expression of IDO was linked with favourable prognosis. [19,46] Further studies are required in view of the contradictory findings, to comprehend this complex role of IDO in various cancers.…”

Section: Ido As An Immunotherapeutic Targetmentioning

confidence: 99%

Indoleamine 2,3 Dioxygenase as an Immunotherapeutic Target Brings a New Hope for Cancer Patients

Asghar

Loya

2018

J Cancer Allied Spec

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Therapeutic manipulation of immune system in cancer has been an extensive area of research in the field of oncoimmunology. Immunotherapy helps the immune system to combat against cancer. Tumour cells take an edge of immunosuppressive mechanisms and inhibit antitumour immune responses. Indoleamine 2,3 dioxygenase (IDO) is an immunosuppressive enzyme which is involved in tumour immune escape mechanism in various cancers. IDO can degrade the tryptophan into kynurenines and has an ability to enhance the immune tolerance through mammalian target of rapamycin pathway general control nonderepressible 2 (GCN2) pathway and induction of regulatory T (T-regs) cells. IDO-induced T-regs suppress the local immune responses in the tumour microenvironment and promote metastasis. IDO overexpression in various cancers is associated with poor prognosis. Several preclinical and clinical trials have been proceeding and recommend that IDO inhibitor may be an influential tool against a wide range of cancers. IDO inhibitors as adjuvant therapeutic agents may also have clinical implications. Thus, IDO has the potential to be used as an immunotherapeutic target. This review discusses the promising role of IDO in cancer and its implication in immunotherapy.Key words: Breast cancer, colorectal cancer, haematological malignancies, immunotherapy, indoleamine 2,3-dioxygenase, pancreatic cancer, prostate cancer

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Indoleamine 2,3-dioxygenase Affects the Aggressiveness of Intraductal Papillary Mucinous Neoplasms Through Foxp3+CD4+CD25+ T Cells in Peripheral Blood

Abstract: Peripheral Foxp3(+) Tregs accurately reflect the aggressiveness of IPMNs. An increase in Foxp3(+) Tregs can be induced by local IDO-positive cells in IPMN.

Cited by 16 publications

References 15 publications

Interferon Gamma Suppresses Collagen-Induced Arthritis by Regulation of Th17 through the Induction of Indoleamine-2,3-Deoxygenase

Interferon Gamma Suppresses Collagen-Induced Arthritis by Regulation of Th17 through the Induction of Indoleamine-2,3-Deoxygenase

Peripheral Tr1 and Foxp3+ Treg as Markers of Recurrent Malignancies in Patients with Hepato-Biliary Pancreatic Cancers

Indoleamine 2,3 Dioxygenase as an Immunotherapeutic Target Brings a New Hope for Cancer Patients

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