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Characterization of the in vivo immune network of IDO, tryptophan metabolism, PD-L1, and CTLA-4 in circulating immune cells in melanoma

INES CHEVOLET (UGent) , Reinhart Speeckaert (UGent) , Max Schreuer (UGent) , B Neyns, Olga Krysko (UGent) , Claus Bachert (UGent) , B Hennart, D Allorge, Nanja van Geel (UGent) , Mireille Van Gele (UGent) , et al.
(2015) ONCOIMMUNOLOGY. 4(3).
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Abstract
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(+) 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 = 0.027). Tryptophan breakdown confirmed the functional activity of IDO and was linked with increased PD-L1+ cytotoxic T-cells (p = 0.009), relative lymphopenia (p = 0.036), and a higher mDC/pDC ratio (p = 0.002). High levels of circulating PD-L1+ cytotoxic T-cells were associated with increased CTLA-4 expression by Tregs (p = 0.005) and MDSC levels (p = 0.033). This illustrates that counter-regulatory immune mechanisms in melanoma should be considered as one interrelated signaling network. Moreover, both increased PD-L1+ 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 IDO+ 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.
Keywords
ASSOCIATION, IPILIMUMAB, IMMUNOTHERAPY, CANCER, CATABOLISM, DENDRITIC CELLS, SUPPRESSOR-CELLS, INTERFERON-GAMMA, 3-DIOXYGENASE, INDOLEAMINE 2, REGULATORY T-CELLS, regulatory T-cells, programmed-death ligand 1 (PD-L1), prognosis, negative feedback mechanism, melanoma, indoleamine 2-3-dioxygenase (IDO), cytotoxic T lymphocyte-associated antigen 4 (CTLA-4)

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MLA
CHEVOLET, INES et al. “Characterization of the in Vivo Immune Network of IDO, Tryptophan Metabolism, PD-L1, and CTLA-4 in Circulating Immune Cells in Melanoma.” ONCOIMMUNOLOGY 4.3 (2015): n. pag. Print.
APA
CHEVOLET, I., Speeckaert, R., Schreuer, M., Neyns, B., Krysko, O., Bachert, C., Hennart, B., et al. (2015). Characterization of the in vivo immune network of IDO, tryptophan metabolism, PD-L1, and CTLA-4 in circulating immune cells in melanoma. ONCOIMMUNOLOGY, 4(3).
Chicago author-date
CHEVOLET, INES, Reinhart Speeckaert, Max Schreuer, B Neyns, Olga Krysko, Claus Bachert, B Hennart, et al. 2015. “Characterization of the in Vivo Immune Network of IDO, Tryptophan Metabolism, PD-L1, and CTLA-4 in Circulating Immune Cells in Melanoma.” Oncoimmunology 4 (3).
Chicago author-date (all authors)
CHEVOLET, INES, Reinhart Speeckaert, Max Schreuer, B Neyns, Olga Krysko, Claus Bachert, B Hennart, D Allorge, Nanja van Geel, Mireille Van Gele, and Lieve Brochez. 2015. “Characterization of the in Vivo Immune Network of IDO, Tryptophan Metabolism, PD-L1, and CTLA-4 in Circulating Immune Cells in Melanoma.” Oncoimmunology 4 (3).
Vancouver
1.
CHEVOLET I, Speeckaert R, Schreuer M, Neyns B, Krysko O, Bachert C, et al. Characterization of the in vivo immune network of IDO, tryptophan metabolism, PD-L1, and CTLA-4 in circulating immune cells in melanoma. ONCOIMMUNOLOGY. 2015;4(3).
IEEE
[1]
I. CHEVOLET et al., “Characterization of the in vivo immune network of IDO, tryptophan metabolism, PD-L1, and CTLA-4 in circulating immune cells in melanoma,” ONCOIMMUNOLOGY, vol. 4, no. 3, 2015.
@article{5973466,
  abstract     = {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(+) 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 = 0.027). Tryptophan breakdown confirmed the functional activity of IDO and was linked with increased PD-L1+ cytotoxic T-cells (p = 0.009), relative lymphopenia (p = 0.036), and a higher mDC/pDC ratio (p = 0.002). High levels of circulating PD-L1+ cytotoxic T-cells were associated with increased CTLA-4 expression by Tregs (p = 0.005) and MDSC levels (p = 0.033). This illustrates that counter-regulatory immune mechanisms in melanoma should be considered as one interrelated signaling network. Moreover, both increased PD-L1+ 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 IDO+ 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.},
  articleno    = {e982382},
  author       = {CHEVOLET, INES and Speeckaert, Reinhart and Schreuer, Max and Neyns, B and Krysko, Olga and Bachert, Claus and Hennart, B and Allorge, D and van Geel, Nanja and Van Gele, Mireille and Brochez, Lieve},
  issn         = {2162-402X},
  journal      = {ONCOIMMUNOLOGY},
  keywords     = {ASSOCIATION,IPILIMUMAB,IMMUNOTHERAPY,CANCER,CATABOLISM,DENDRITIC CELLS,SUPPRESSOR-CELLS,INTERFERON-GAMMA,3-DIOXYGENASE,INDOLEAMINE 2,REGULATORY T-CELLS,regulatory T-cells,programmed-death ligand 1 (PD-L1),prognosis,negative feedback mechanism,melanoma,indoleamine 2-3-dioxygenase (IDO),cytotoxic T lymphocyte-associated antigen 4 (CTLA-4)},
  language     = {eng},
  number       = {3},
  pages        = {8},
  title        = {Characterization of the in vivo immune network of IDO, tryptophan metabolism, PD-L1, and CTLA-4 in circulating immune cells in melanoma},
  url          = {http://dx.doi.org/10.4161/2162402X.2014.982382},
  volume       = {4},
  year         = {2015},
}

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