Regimen-Dependent Anti-Cytokine and Immune-Checkpoint Autoantibodies Are Associated with Immunotherapy Toxicity and Response in Melanoma
16 affiliations
- 1Department of Dermatology, University Hospital Heidelberg and National Center for Tumor Diseases (NCT), NCT Heidelberg, a Partnership Between DKFZ and University Hospital Heidelberg, 69120 Heidelberg, Germany
- 2German Cancer Consortium (DKTK), Core Center DKFZ Heidelberg, 69120 Heidelberg, Germany
- 3Medical Faculty, University Heidelberg, 69120 Heidelberg, Germany
- 4German Cancer Research Center (DKFZ), Applied Tumor Immunity, 69120 Heidelberg, Germany
- 5Alden Scientific Immune GmbH, 44227 Dortmund, Germany
- 6Department of Dermatology, University Hospital Zürich, 8091 Zürich, Switzerland
- 7Faculty of Medicine, University of Zürich, 8006 Zürich, Switzerland
- 8Department of Dermatology, University Hospital Zürich, University of Zürich, 8091 Zürich, Switzerland
- 9Department of Dermatology, Kantonsspital Aarau, 5001 Aarau, Switzerland
- 10Department of Dermatology, University Hospital Homburg/Saar, 66421 Homburg Saar, Germany
- 11Department of Dermatology, University Hospital Tübingen, 72076 Tübingen, Germany
- 12Skin Cancer Unit, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- 13Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, 68167 Mannheim, Germany
- 14DKFZ Hector Cancer Institute at the University Medical Center Mannheim, 68167 Mannheim, Germany
- 15Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany
- 16Skin Cancer Center at the University Cancer Center and National Center for Tumor Diseases Dresden, Department of Dermatology, University Hospital Carl Gustav Carus Dresden, 01307 Dresden, Germany
Abstract
Immune checkpoint inhibitor (ICI) efficacy and immune-related adverse events (irAEs) in melanoma are influenced by the pre-treatment immune state. We investigated whether baseline autoantibodies directed against cytokines, chemokines, cytokine receptors, and immune-checkpoint/costimulatory proteins were associated with outcome in a regimen-dependent manner. Baseline sera from patients with metastatic melanoma were profiled on a multiplex bead array of 86 cytokine, chemokine, cytokine-receptor and immune-checkpoint antigens, and associations with best overall response and irAE development were assessed within pre-specified treatment strata by label-permutation testing with Benjamini–Hochberg false-discovery-rate control (SAM as a sensitivity analysis). Associations differed by ICI regimen. Anti-IL17A and anti-CCL2 reactivity was higher in patients developing irAEs under ipilimumab monotherapy (both p = 0.003) and shifted in the opposite direction under pembrolizumab without prior CTLA-4 therapy. Higher anti-PD-L1/CD274 and anti-CCL5 and lower anti-KIT reactivity were associated with response to pembrolizumab without prior CTLA-4 therapy (p = 0.025, p = 0.002, p = 0.006), and lower anti-MCAM and anti-CSF3 reactivity with response under ipilimumab/nivolumab (p = 0.001 and p = 0.002). No association survived false-discovery-rate correction, so all findings are exploratory and hypothesis-generating; higher baseline anti-IL10 reactivity was a leading irAE signal under pembrolizumab without prior CTLA-4 therapy (p = 0.027). These regimen-dependent humoral markers warrant prospective, regimen-stratified validation.
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BibTeX
@article{reschke2026regimendependent,
title = {{Regimen-Dependent Anti-Cytokine and Immune-Checkpoint Autoantibodies Are Associated with Immunotherapy Toxicity and Response in Melanoma}},
author = {Robin Reschke and Hans-Dieter Zucht and Petra Budde and Joanna Mangana and Reinhard Dummer and Claudia Pföhler and Kilian Wistuba-Hamprecht and Benjamin Weide and Friedegund Meier and Lara-Elena Hakim-Meibodi and Carsten Schulz and Jasmin Richter and Alexander H. Enk and Manuel Bräutigam and Thi Nhat Minh Nguyen and Jessica C. Hassel},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27219746},
url = {https://www.mdpi.com/1422-0067/27/21/9746},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Regimen-Dependent Anti-Cytokine and Immune-Checkpoint Autoantibodies Are Associated with Immunotherapy Toxicity and Response in Melanoma
AU - Robin Reschke
AU - Hans-Dieter Zucht
AU - Petra Budde
AU - Joanna Mangana
AU - Reinhard Dummer
AU - Claudia Pföhler
AU - Kilian Wistuba-Hamprecht
AU - Benjamin Weide
AU - Friedegund Meier
AU - Lara-Elena Hakim-Meibodi
AU - Carsten Schulz
AU - Jasmin Richter
AU - Alexander H. Enk
AU - Manuel Bräutigam
AU - Thi Nhat Minh Nguyen
AU - Jessica C. Hassel
PY - 2026
DA - 2026/10/30
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27219746
UR - https://www.mdpi.com/1422-0067/27/21/9746
AB - Immune checkpoint inhibitor (ICI) efficacy and immune-related adverse events (irAEs) in melanoma are influenced by the pre-treatment immune state. We investigated whether baseline autoantibodies directed against cytokines, chemokines, cytokine receptors, and immune-checkpoint/costimulatory proteins were associated with outcome in a regimen-dependent manner. Baseline sera from patients with metastatic melanoma were profiled on a multiplex bead array of 86 cytokine, chemokine, cytokine-receptor and immune-checkpoint antigens, and associations with best overall response and irAE development were assessed within pre-specified treatment strata by label-permutation testing with Benjamini–Hochberg false-discovery-rate control (SAM as a sensitivity analysis). Associations differed by ICI regimen. Anti-IL17A and anti-CCL2 reactivity was higher in patients developing irAEs under ipilimumab monotherapy (both p = 0.003) and shifted in the opposite direction under pembrolizumab without prior CTLA-4 therapy. Higher anti-PD-L1/CD274 and anti-CCL5 and lower anti-KIT reactivity were associated with response to pembrolizumab without prior CTLA-4 therapy (p = 0.025, p = 0.002, p = 0.006), and lower anti-MCAM and anti-CSF3 reactivity with response under ipilimumab/nivolumab (p = 0.001 and p = 0.002). No association survived false-discovery-rate correction, so all findings are exploratory and hypothesis-generating; higher baseline anti-IL10 reactivity was a leading irAE signal under pembrolizumab without prior CTLA-4 therapy (p = 0.027). These regimen-dependent humoral markers warrant prospective, regimen-stratified validation.
SN - 1422-0067
ER -