Interleukin 17 signaling supports clinical benefit of dual CTLA-4 and PD-1 checkpoint inhibition in melanoma
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Published:2023-07-31
Issue:9
Volume:4
Page:1292-1308
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ISSN:2662-1347
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Container-title:Nature Cancer
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language:en
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Short-container-title:Nat Cancer
Author:
Váraljai RenátaORCID, Zimmer Lisa, Al-Matary Yahya, Kaptein Paulien, Albrecht Lea J., Shannan Batool, Brase Jan C., Gusenleitner Daniel, Amaral Teresa, Wyss Nina, Utikal Jochen, Flatz Lukas, Rambow Florian, Reinhardt Hans Christian, Dick JennyORCID, Engel Daniel R., Horn Susanne, Ugurel Selma, Sondermann WiebkeORCID, Livingstone Elisabeth, Sucker Antje, Paschen AnnetteORCID, Zhao FangORCID, Placke Jan M., Klose Jasmin M., Fendler Wolfgang P., Thommen Daniela S.ORCID, Helfrich Iris, Schadendorf DirkORCID, Roesch AlexanderORCID
Abstract
AbstractRecent 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.
Funder
Deutsche Forschungsgemeinschaft Novartis | Novartis Pharma Brigitte und Dr. Konstanze Wegener-Stiftung
Publisher
Springer Science and Business Media LLC
Subject
Cancer Research,Oncology
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