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

Publication

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

Journal Paper/Review - Jul 31, 2023

Váraljai Renáta, 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 Jenny, Engel Daniel R, Horn Susanne, Ugurel Selma, Sondermann Wiebke, Livingstone Elisabeth, Sucker Antje, Paschen Annette, Zhao Fang, Placke Jan M, Klose Jasmin M, Fendler Wolfgang Peter, Thommen Daniela S, Helfrich Iris, Schadendorf Dirk, Roesch Alexander

Citation

Váraljai R, Zimmer L, Al-Matary Y, Kaptein P, Albrecht L, Shannan B, Brase J, Gusenleitner D, Amaral T, Wyss N, Utikal J, Flatz L, Rambow F, Reinhardt H, Dick J, Engel D, Horn S, Ugurel S, Sondermann W, Livingstone E, Sucker A, Paschen A, Zhao F, Placke J, Klose J, Fendler W, Thommen D, Helfrich I, Schadendorf D, Roesch A. Interleukin 17 signaling supports clinical benefit of dual CTLA-4 and PD-1 checkpoint inhibition in melanoma. Nat Cancer 2023; 4:1292-1308.

Type

Journal Paper/Review (English)

Journal

Nat Cancer 2023; 4

Publication Date

Jul 31, 2023

Issn Electronic

2662-1347

Pages

1292-1308

Brief description/objective

Recent studies suggest that BRAF-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 (T17) gene expression signatures (GES) in BRAF-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-T17 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 T17 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.