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Interleukin 17 signaling supports clinical benefit of dual CTLA-4 and PD-1 checkpoint inhibition in melanoma

Recent studies suggest that BRAFV600-mutated melanomas in particular respond to dual anti-programmed cell death protein 1 (PD-1) and anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) immune checkpoint inhibition (ICI). Here we identified an over-representation of interleukin (IL)-17-type 17...

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Hauptverfasser: Váraljai, Renáta (VerfasserIn) , Zimmer, Lisa (VerfasserIn) , Al-Matary, Yahya (VerfasserIn) , Kaptein, Paulien (VerfasserIn) , Albrecht, Lea J. (VerfasserIn) , Shannan, Batool (VerfasserIn) , Brase, Jan C. (VerfasserIn) , Gusenleitner, Daniel (VerfasserIn) , Amaral, Teresa (VerfasserIn) , Wyss, Nina (VerfasserIn) , Utikal, Jochen (VerfasserIn) , Flatz, Lukas (VerfasserIn) , Rambow, Florian (VerfasserIn) , Reinhardt, Hans Christian (VerfasserIn) , Dick, Jenny (VerfasserIn) , Engel, Daniel R. (VerfasserIn) , Horn, Susanne (VerfasserIn) , Ugurel, Selma (VerfasserIn) , Sondermann, Wiebke (VerfasserIn) , Livingstone, Elisabeth (VerfasserIn) , Sucker, Antje (VerfasserIn) , Paschen, Annette (VerfasserIn) , Zhao, Fang (VerfasserIn) , Placke, Jan-Malte (VerfasserIn) , Klose, Jasmin M. (VerfasserIn) , Fendler, Wolfgang P. (VerfasserIn) , Thommen, Daniela S. (VerfasserIn) , Helfrich, Iris (VerfasserIn) , Schadendorf, Dirk (VerfasserIn) , Roesch, Alexander (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: September 2023
In: Nature cancer
Year: 2023, Jahrgang: 4, Heft: 9, Pages: 1292-1308
ISSN:2662-1347
DOI:10.1038/s43018-023-00610-2
Online-Zugang:Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s43018-023-00610-2
Verlag, kostenfrei, Volltext: https://www.nature.com/articles/s43018-023-00610-2
Volltext
Verfasserangaben:Renáta Váraljai, Lisa Zimmer, Yahya Al-Matary, Paulien Kaptein, Lea J. Albrecht, Batool Shannan, Jan C. Brase, Daniel Gusenleitner, Teresa Amaral, Nina Wyss, Jochen Utikal, Lukas Flatz, Florian Rambow, Hans Christian Reinhardt, Jenny Dick, Daniel R. Engel, Susanne Horn, Selma Ugurel, Wiebke Sondermann, Elisabeth Livingstone, Antje Sucker, Annette Paschen, Fang Zhao, Jan M. Placke, Jasmin M. Klose, Wolfgang P. Fendler, Daniela S. Thommen, Iris Helfrich, Dirk Schadendorf & Alexander Roesch
Beschreibung
Zusammenfassung:Recent studies suggest that BRAFV600-mutated melanomas in particular respond to dual anti-programmed cell death protein 1 (PD-1) and anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) immune checkpoint inhibition (ICI). Here we identified an over-representation of interleukin (IL)-17-type 17 helper T (TH17) gene expression signatures (GES) in BRAFV600-mutated tumors. Moreover, high baseline IL-17 GES consistently predicted clinical responses in dual-ICI-treated patient cohorts but not in mono anti-CTLA-4 or anti-PD-1 ICI cohorts. High IL-17 GES corresponded to tumor infiltration with T cells and neutrophils. Accordingly, high neutrophil infiltration correlated with clinical response specifically to dual ICI, and tumor-associated neutrophils also showed strong IL-17-TH17 pathway activity and T cell activation capacity. Both the blockade of IL-17A and the depletion of neutrophils impaired dual-ICI response and decreased T cell activation. Finally, high IL-17A levels in the blood of patients with melanoma indicated a higher global TH17 cytokine profile preceding clinical response to dual ICI but not to anti-PD-1 monotherapy, suggesting a future role as a biomarker for patient stratification.
Beschreibung:Online veröffentlicht: 31. Juli 2023
Gesehen am 08.10.2024
Beschreibung:Online Resource
ISSN:2662-1347
DOI:10.1038/s43018-023-00610-2

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