Interleukin 17 signaling supports clinical benefit of dual CTLA-4 and PD-1 checkpoint inhibition in melanoma
Renáta Váraljai, Lisa Zimmer, Yahya Al-Matary, Paulien Kaptein, Lea Jessica Albrecht, Batool Shannan, Jan C. Brase, Daniel Gusenleitner, Teresa Amaral, Nina Wyss, Jochen Utikal, Lukas Flatz, Florian Rambow, Hans Christian Reinhardt, Jenny Bottek, Daniel R. Engel, Susanne Horn, Selma Ugurel, Wiebke Sondermann, Elisabeth Livingstone, Antje Sucker, Annette Paschen, Fang Zhao, Jan M. Placke, Jasmin Klose, Wolfgang P. Fendler, Daniela S. Thommen, Iris Helfrich, Dirk Schadendorf, Alexander Roesch
Abstract
Abstract Recent studies suggest that BRAF V600 -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 (T H 17) gene expression signatures (GES) in BRAF V600 -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–T H 17 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 T H 17 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.