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

Váraljai R, Zimmer L, Al-Matary Y, Kaptein P, Albrecht LJ, Shannan B, Brase JC, Gusenleitner D, Amaral T, Wyss N, Utikal J, Flatz L, Rambow F, Reinhardt HC, Dick J, Engel DR, Horn S, Ugurel S, Sondermann W, Livingstone E, Sucker A, Paschen A, Zhao F, Placke JM, Klose JM, Fendler WP, Thommen DS, Helfrich I, Schadendorf D, Roesch A (2023)

Publication Type: Journal article

Publication year: 2023

Journal

Nature Cancer Springer Nature

Book Volume: 4

Pages Range: 1292-1308

Journal Issue: 9

DOI: 10.1038/s43018-023-00610-2

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 (TH17) 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–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.

Involved external institutions

Universitätsklinikum Essen DE Germany (DE) Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital (NKI / NKI-AVL) NL Netherlands (NL) Novartis AG CH Switzerland (CH) Novartis Institutes for BioMedical Research, Inc. US United States (USA) (US) Universitätsklinikum Tübingen DE Germany (DE) Kantonsspital St.Gallen CH Switzerland (CH) Deutsches Krebsforschungszentrum (DKFZ) DE Germany (DE)

How to cite

APA:

Váraljai, R., Zimmer, L., Al-Matary, Y., Kaptein, P., Albrecht, L.J., Shannan, B.,... Roesch, A. (2023). Interleukin 17 signaling supports clinical benefit of dual CTLA-4 and PD-1 checkpoint inhibition in melanoma. Nature Cancer, 4(9), 1292-1308. https://doi.org/10.1038/s43018-023-00610-2

MLA:

Váraljai, Renáta, et al. "Interleukin 17 signaling supports clinical benefit of dual CTLA-4 and PD-1 checkpoint inhibition in melanoma." Nature Cancer 4.9 (2023): 1292-1308.

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