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

Media type: E-Article

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

Contributor: Váraljai, Renáta [Author]; Zimmer, Lisa [Author]; Al-Matary, Yahya [Author]; Kaptein, Paulien [Author]; Albrecht, Lea J. [Author]; Shannan, Batool [Author]; Brase, Jan C. [Author]; Gusenleitner, Daniel [Author]; Amaral, Teresa [Author]; Wyss, Nina [Author]; Utikal, Jochen [Author]; Flatz, Lukas [Author]; Rambow, Florian [Author]; Reinhardt, Hans Christian [Author]; Dick, Jenny [Author]; Engel, Daniel R. [Author]; Horn, Susanne [Author]; Ugurel, Selma [Author]; Sondermann, Wiebke [Author]; Livingstone, Elisabeth [Author]; Sucker, Antje [Author]; Paschen, Annette [Author]; Zhao, Fang [Author]; Placke, Jan-Malte [Author]; Klose, Jasmin M. [Author]; Fendler, Wolfgang P. [Author]; Thommen, Daniela S. [Author]; Helfrich, Iris [Author]; Schadendorf, Dirk [Author]; Roesch, Alexander [Author]

Published: September 2023

Language: English

DOI: 10.1038/s43018-023-00610-2

Identifier:

Keywords: Cancer ; Cancer immunotherapy ; Melanoma ; Tumour immunology

Origination:

Footnote: Online veröffentlicht: 31. Juli 2023

Description: 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.

Access State: Open Access

Search in field:

Recently searched for: