Peritumoral indoleamine 2,3‐dioxygenase expression in melanoma: an early marker of resistance to immune control?

Chevolet, Inès; Speeckaert, Reinhart; Haspeslagh, Marc; Neyns, Bart; Krüse, Vibeke; Schreuer, Max; Gele, Mireille Van; Geel, Nanja van; Brochez, Liève

doi:10.1111/bjd.13100

Cited by 56 publications

(70 citation statements)

References 36 publications

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“…This clustering of IDO expression in the sentinel and in PBMCs is remarkable, as we previously showed that IDO expression is also consistent in the primary, sentinel, and even metastatic tissue of melanoma patients. 8 Our results indicate that IDO expression by host cells is important in the pathogenesis of melanoma, but the question remains how this IDO expression is induced. Soluble tumorderived factors could be responsible, but alternatively this clustering could also indicate a certain patient-related predisposition.…”

Section: Discussionmentioning

confidence: 75%

“…Therefore, the sentinel lymph nodes of the included patients were immunohistochemically stained for IDO and assessed as previously reported. 8 Remarkably, patients with an IDO-positive sentinel had more circulating IDO-positive PBMCs (cultured, unstimulated cells, p D 0.016). This could be attributed to higher levels of IDOC mMDSCs ( Table 5, lower part), which were found to be associated with IDO status of the sentinel (p D 0.018).…”

Section: Pd-l1mentioning

confidence: 96%

“…7 We were previously able to show that IDO expression in the primary tumor or sentinel lymph node has an independent negative prognostic effect on overall and relapse-free survival in melanoma. 8,9 Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) is a target gene of FoxP3 and is constitutively expressed by Tregs. It has a major physiological role in enhancing Treg activity and downmodulating T helper cell activity, by competing with CD28 for binding with CD80.…”

Section: Introductionmentioning

confidence: 99%

“…We previously demonstrated an increased mean-fluorescence intensity (MFI) for IDO in peripheral blood mononuclear cells (PBMCs) of melanoma patients with advanced disease after stimulation with CTLA-4. 8 In the present study, we investigated the in vivo expression of IDO, PD-L1 and CTLA-4 by immune cells of the lymphoid and myeloid lineage in the peripheral blood of stage I-IV melanoma patients. To ascertain the functional relevance of the detected IDO, tryptophan metabolism was assessed by ultraperformance liquid chromatography (UPLC).…”

Section: Introductionmentioning

confidence: 99%

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Characterization of thein vivoimmune network of IDO, tryptophan metabolism, PD-L1, andCTLA-4in circulating immune cells in melanoma

et al. 2015

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In melanoma, both the induction of immunosuppression by tumor cells and the inflammatory antitumor response can induce an upregulation of counter-regulatory mechanisms such as indoleamine 2,3-dioxygenase (IDO), programmed death-ligand 1 (PD-L1) and CTLA-4 C regulatory T-cells (Tregs) in the tumor microenvironment. Even though these immunosuppressive mediators are targets for immunotherapy, research investigating their expression in the peripheral blood is lacking. We therefore, performed flow cytometry on PBMCs of stage I-IV melanoma patients. IDO expression was detected in plasmacytoid dendritic cells (pDC) and monocytic myeloid-derived suppressor cells (mMDSC), and increased in advanced disease stage (p D 0.027). Tryptophan breakdown confirmed the functional activity of IDO and was linked with increased PD-L1C cytotoxic T-cells (p D 0.009), relative lymphopenia (p D 0.036), and a higher mDC/pDC ratio (p D 0.002). High levels of circulating PD-L1C cytotoxic T-cells were associated with increased CTLA-4 expression by Tregs (p D 0.005) and MDSC levels (p D 0.033). This illustrates that counter-regulatory immune mechanisms in melanoma should be considered as one interrelated signaling network. Moreover, both increased PD-L1C T-cells and CTLA-4 expression in Tregs conferred a negative prognosis, indicating their in vivo relevance. Remarkably, circulating CTLA-4, IDO, and pDC levels were altered according to prior invasion of the sentinel lymph node and IDO expression in the sentinel was associated with more IDOC PBMCs. We conclude that the expression of IDO, PD-L1, and CTLA-4 in the peripheral blood of melanoma patients is strongly interconnected, associated with advanced disease and negative outcome, independent of disease stage. Combination treatments targeting several of these markers are therefore likely to exert a synergistic response.

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Section: Discussionmentioning

confidence: 75%

Section: Pd-l1mentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Characterization of thein vivoimmune network of IDO, tryptophan metabolism, PD-L1, andCTLA-4in circulating immune cells in melanoma

et al. 2015

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“…They observed better OS (p = 0.04) in patients who demonstrated elevated expression of IDO in both the primary tumors and lymph nodes, independently. Worth noticing is the fact that the better prognosis of patients with lower nodal IDO expression was independent of whether the nodes were metastatic or not [14]. Speckaert et al analyzed 116 sentinel lymph nodes from melanoma patients using IHC and flow cytometry.…”

Section: Discussionmentioning

confidence: 99%

The prognostic significance of indoleamine-2,3-dioxygenase and the receptors for transforming growth factor β and interferon γ in metastatic lymph nodes in malignant melanoma

Pelak¹,

Śnietura²,

Lange³

et al. 2015

pjp

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We analyzed the prognostic significance of indoleamine-2,3-dioxygenase (IDO) and type 1 receptors for transforming growth factor beta (TGF-βR1) and interferon gamma (IFN-γR1) in resected nodal metastases of 48 malignant melanoma patients. In 32 cases the corresponding skin tumors were available. We used immunohistochemical (IHC) staining which was assessed by pathologists and by a computer-aided algorithm that yielded quantitative results, both absolute and relative. We correlated the results with the patient outcome. We identified absolute computer-assessed IDO levels as positively correlated with increased risk of death in a multivariate model (HR = 1.02; 95% CI: 1.002-1.04; p = 0.03). In univariate analysis, patients with IDO levels below the median had a better overall survival time (30.3 vs. 17.5 months; p = 0.03). TGF-βR1 and IFN-γR1 expression was modestly correlated (R = 0.34; p < 0.05) and TGF-βR1 expression was lower in lymph nodes than in matched primary skin tumors (Z = 2.87; p = 0.004). The pathologists' and computer-aided IHC assessment demonstrated high correlation levels (R = 0.61, R = 0.74 and R = 0.88 for IDO, TGF-βR1 and IFN-γR1, respectively). Indoleamine-2,3-dioxygenase is prognostic for the patient outcome in melanoma with nodal involvement and should be investigated prospectively for its predictive significance. IHC assessment by computer-aided methods is recommended as its gives IHC more objectivity and reproducibility.

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Indoleamine 2,3-Dioxygenase (IDO) and Cancerous Cells

Safdarian

Farhangnia

Rezaei

2023

Handbook of Cancer and Immunology

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Peritumoral indoleamine 2,3‐dioxygenase expression in melanoma: an early marker of resistance to immune control?

Cited by 56 publications

References 36 publications

Characterization of thein vivoimmune network of IDO, tryptophan metabolism, PD-L1, andCTLA-4in circulating immune cells in melanoma

Characterization of thein vivoimmune network of IDO, tryptophan metabolism, PD-L1, andCTLA-4in circulating immune cells in melanoma

The prognostic significance of indoleamine-2,3-dioxygenase and the receptors for transforming growth factor β and interferon γ in metastatic lymph nodes in malignant melanoma

Indoleamine 2,3-Dioxygenase (IDO) and Cancerous Cells

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