Indoleamine 2,3‐dioxygenase 2 depletion suppresses tumor growth in a mouse model of Lewis lung carcinoma

Yamasuge, Wakana; Yamamoto, Yorimasa; Fujigaki, Hidetsugu; Hoshi, Masato; Nakamoto, Kentaro; Kunisawa, Kazuo; Mouri, Akihiro; Nabeshima, Toshitaka

doi:10.1111/cas.14179

Cited by 26 publications

(18 citation statements)

References 39 publications

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“…LLC was separated from spontaneous epidermal cancer of the lungs of a mouse in 1951, and has since been used to set up animal models with tumor [ 34 ]. It is a rapidly growing tumor and a very malignant type of epidermoid carcinoma [ 35 , 36 ]. LLC is a murine tumor, and we have experimented with LCC cells because the tumor grows well in a mouse and is easy to experiment without using a special mouse such as a nude mouse with reduced immunity.…”

Section: Discussionmentioning

confidence: 99%

“…LLC is a murine tumor, and we have experimented with LCC cells because the tumor grows well in a mouse and is easy to experiment without using a special mouse such as a nude mouse with reduced immunity. However, because LLC cells are cancer cells that grow only in mice and the proliferation rate may be faster than other cancer cells [ 34 , 35 , 36 ], which may affect the experimental results.…”

Section: Discussionmentioning

confidence: 99%

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Effects of Sevoflurane on Lewis Lung Carcinoma Cell Proliferation In Vivo and In Vitro

et al. 2021

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Background and objectives: There are several studies that sevoflurane could enhance proliferation of cancer cells, while others suggest no effect on clinical outcome. We conducted in vivo and in vitro experiments to investigate the effects of sevoflurane, a volatile anesthetic, on proliferation and outcomes of Lewis lung carcinoma (LLC) cells. Materials and Methods: A total of 37 mice were injected with LLC cells to compare the tumor size and survival of the sevoflurane exposed group (sevo group) and control group. The sevo group was exposed to 2% sevoflurane and 4 L/min of oxygen for 1 h per day 3 times per week, and the control group was exposed only to 4 L/min of oxygen. In vitro study, 12 plates incubated with LCC cells. 6 plates were exposed to 2% sevoflurane for 1 hr/day for 3 days and 6 plates were not exposed, and cell proliferation was compared after 3 days. Results: There were no significant differences in survival or tumor size between mice exposed to sevoflurane and control mice (survival: 29.06 ± 4.45 vs. 28.76 ± 3.75, p = 0.836; tumor size: 0.75 (0.41–1.02) vs. 0.49 (0.11–0.79), p = 0.153). However, in vitro study, the proliferation of LLC cells exposed to sevoflurane increased by 9.2% compared to the control group (p = 0.018). Conclusions: Sevoflurane (2 vol%) exposure could promote proliferation of LLC cells in vitro environment, but may not affect proliferation of LLC cells in vivo environment. These results suggest that in vitro studies on the effects of anesthetics on cancer may differ from those of in vivo or clinical studies.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Effects of Sevoflurane on Lewis Lung Carcinoma Cell Proliferation In Vivo and In Vitro

et al. 2021

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“…Therefore, when injecting LLC cells into IDO2 KO mice, no IDO2 will be present anywhere in the organism. In these conditions, tumor growth is suppressed, IFN-g secretion is enhanced in the tumor bed, and the number of CD8 + tumor infiltrating lymphocytes (TILs) is increased (28).…”

Section: Ido2 In Mouse Tumorsmentioning

confidence: 99%

Current Challenges for IDO2 as Target in Cancer Immunotherapy

et al. 2021

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Immune checkpoint inhibitors have revolutionized the clinical approach of untreatable tumors and brought a breath of fresh air in cancer immunotherapy. However, the therapeutic effects of these drugs only cover a minority of patients and alternative immunotherapeutic targets are required. Metabolism of l-tryptophan (Trp) via the kynurenine pathway represents an important immune checkpoint mechanism that controls adaptive immunity and dampens exaggerated inflammation. Indoleamine 2,3-dioxygenase 1 (IDO1), the enzyme catalyzing the first, rate–limiting step of the pathway, is expressed in several human tumors and IDO1 catalytic inhibitors have reached phase III clinical trials, unfortunately with disappointing results. Although much less studied, the IDO1 paralog IDO2 may represent a valid alternative as drug target in cancer immunotherapy. Accumulating evidence indicates that IDO2 is much less effective than IDO1 in metabolizing Trp and its functions are rather the consequence of interaction with other, still undefined proteins that may vary in distinct inflammatory and neoplastic contexts. As a matter of fact, the expression of IDO2 gene variants is protective in PDAC but increases the risk of developing tumor in NSCLC patients. Therefore, the definition of the IDO2 interactome and function in distinct neoplasia may open innovative avenues of therapeutic interventions.

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“…IDO2 was required for T regulatory cell activation under the same assay conditions that IDO1 was shown to be critical ( 8 ). However, IDO2's effect on tumor development is ambiguous, with data supporting both immunoregulatory ( 28 ) and proinflammatory roles ( 29 ) depending on the model used. Likewise, the requirement for IDO2 in normal immune function is not known.…”

Section: Introductionmentioning

confidence: 99%

Differential Roles of IDO1 and IDO2 in T and B Cell Inflammatory Immune Responses

et al. 2020

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Indoleamine-2,3-dioxygenase (IDO)1 and IDO2 are two closely related tryptophan catabolizing enzymes encoded by linked genes. The IDO pathway is also immunomodulatory, with IDO1 well-characterized as a mediator of tumor immune evasion. Due to its homology with IDO1, IDO2 has been proposed to have a similar immunoregulatory function. Indeed, IDO2, like IDO1, is necessary for the differentiation of regulatory T cells in vitro . However, compared to IDO1, in vivo studies demonstrated a contrasting role for IDO2, with experiments in preclinical models of autoimmune arthritis establishing a proinflammatory role for IDO2 in mediating B and T cell activation driving autoimmune disease. Given their potentially opposing roles in inflammatory responses, interpretation of results obtained using IDO1 or IDO2 single knockout mice could be complicated by the expression of the other enzyme. Here we use IDO1 and IDO2 single and double knockout (dko) mice to define the differential roles of IDO1 and IDO2 in B cell-mediated immune responses. Autoreactive T and B cell responses and severity of joint inflammation were decreased in IDO2 ko, but not IDO1 ko arthritic mice. Dko mice had a reduction in the number of autoantibody secreting cells and severity of arthritis: however, percentages of differentiated T cells and their associated cytokines were not reduced compared to IDO1 ko or wild-type mice. These data suggest that autoreactive B cell responses are mediated by IDO2, while autoreactive T cell responses are indirectly affected by IDO1 expression in the IDO2 ko mice. IDO2 also influenced antibody responses in models of influenza infection and immunization with T cell-independent type II antigens. Taken together, these studies provide evidence for the contrasting roles IDO1 and IDO2 play in immune responses, with IDO1 mediating T cell suppressive effects and IDO2 working directly in B cells as a proinflammatory mediator of B cell responses.

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Indoleamine 2,3‐dioxygenase 2 depletion suppresses tumor growth in a mouse model of Lewis lung carcinoma

Cited by 26 publications

References 39 publications

Effects of Sevoflurane on Lewis Lung Carcinoma Cell Proliferation In Vivo and In Vitro

Effects of Sevoflurane on Lewis Lung Carcinoma Cell Proliferation In Vivo and In Vitro

Current Challenges for IDO2 as Target in Cancer Immunotherapy

Differential Roles of IDO1 and IDO2 in T and B Cell Inflammatory Immune Responses

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