To determine the biomarkers of clinical response to anti-PD-1 and anti-CTLA-4 (dual-ICI) therapy, Váraljai et al. analyzed transcriptional differences between BRAF-mutant versus BRAF-WT melanoma. High baseline IL-17 gene expression signatures were identified in BRAFV600-mutated tumors, which correlated with higher intratumoral infiltration of T cells and neutrophils and predicted clinical response to dual-ICI, but not mono ICI. IL-17A blockade and neutrophil depletion decreased T cell activation and infiltration, and response to dual-ICI in melanoma models. High pre-treatment IL-17A plasma levels predicted response with longer PFS to dual-ICI, but not anti-PD-1 alone in patients with melanoma.
Contributed by Shishir Pant
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.
Author Info: (1) Department of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK), Essen, Germany. (2) Departme
Author Info: (1) Department of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK), Essen, Germany. (2) Department of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK), Essen, Germany. (3) Department of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK), Essen, Germany. (4) Division of Molecular Oncology and Immunology, the Netherlands Cancer Institute, Amsterdam, the Netherlands. (5) Department of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK), Essen, Germany. (6) Department of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK), Essen, Germany. (7) Novartis Pharma AG, Basel, Switzerland. (8) Novartis Institutes for BioMedical Research, Inc., Cambridge, MA, USA. (9) Department of Dermatology, University Hospital of Tbingen, Tbingen, Germany. (10) Institute of Immunobiology, Kantonsspital St. Gallen, Switzerland, Switzerland. (11) Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany. Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht Karls University of Heidelberg, Mannheim, Germany. DKFZ Hector Cancer Institute at the University Medical Center Mannheim, Mannheim, Germany. (12) Department of Dermatology, University Hospital of Tbingen, Tbingen, Germany. Institute of Immunobiology, Kantonsspital St. Gallen, Switzerland, Switzerland. (13) Department of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK), Essen, Germany. Department of Applied Computational Cancer Research, Institute for AI in Medicine (IKIM), University Hospital Essen, Essen, Germany. (14) Department of Hematology and Stem Cell Transplantation, University Hospital Essen, Essen, Germany. Center for Medical Biotechnology (ZMB), University of Duisburg-Essen, Essen, Germany. (15) Department of Immunodynamics, Institute of Experimental Immunology and Imaging, University Hospital Essen, Essen, Germany. (16) Department of Immunodynamics, Institute of Experimental Immunology and Imaging, University Hospital Essen, Essen, Germany. (17) Department of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK), Essen, Germany. Rudolf Schnheimer Institute of Biochemistry, Medical Faculty, University of Leipzig, Leipzig, Germany. (18) Department of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK), Essen, Germany. (19) Department of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK), Essen, Germany. (20) Department of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK), Essen, Germany. (21) Department of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK), Essen, Germany. (22) Department of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK), Essen, Germany. Center for Medical Biotechnology (ZMB), University of Duisburg-Essen, Essen, Germany. (23) Department of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK), Essen, Germany. (24) Department of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK), Essen, Germany. (25) Department of Nuclear Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. (26) Department of Nuclear Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. (27) Division of Molecular Oncology and Immunology, the Netherlands Cancer Institute, Amsterdam, the Netherlands. (28) Department of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK), Essen, Germany. Department of Dermatology and Allergology, Ludwig Maximilian University Munich, Munich, Germany. (29) Department of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK), Essen, Germany. Center for Medical Biotechnology (ZMB), University of Duisburg-Essen, Essen, Germany. NCT West, Campus Essen and University Alliance Ruhr, Research Center One Health, University Duisburg-Essen, Essen, Germany. (30) Department of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK), Essen, Germany. alexander.roesch@uk-essen.de. Center for Medical Biotechnology (ZMB), University of Duisburg-Essen, Essen, Germany. alexander.roesch@uk-essen.de.
