CTLA4 promoter methylation predicts response and progression-free survival in stage IV melanoma treated with anti-CTLA-4
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RESEARCH REPORT
CTLA4 promoter methylation predicts response and progression‑free survival in stage IV melanoma treated with anti‑CTLA‑4 immunotherapy (ipilimumab) Simon Fietz1,2 · Romina Zarbl2 · Dennis Niebel1 · Christian Posch3,4 · Peter Brossart5 · Gerrit H. Gielen6 · Sebastian Strieth2 · Torsten Pietsch6 · Glen Kristiansen7 · Friedrich Bootz2 · Jennifer Landsberg1 · Dimo Dietrich2 Received: 23 July 2020 / Accepted: 20 October 2020 © The Author(s) 2020
Abstract Anti-CTLA-4-antibodies can induce long-lasting tumor remissions. However, only a few patients respond, necessitating the development of predictive companion biomarkers. Increasing evidence suggests a major role of epigenetics, including DNA methylation, in immunology and resistance to immune checkpoint blockade. Here, we tested CTLA4 promoter methylation and CTLA-4 protein expression as predictive biomarkers for response to anti-CTLA-4 immunotherapy. We identified retrospectively N = 30 stage IV melanoma patients treated with single-agent anti-CTLA-4 immunotherapy (ipilimumab). We used quantitative methylation-specific PCR and immunohistochemistry to quantify CTLA4 methylation and protein expression in pre-treatment samples. CTLA4 methylation was significantly higher in progressive as compared to responding tumors and significantly associated with progression-free survival. A subset of infiltrating lymphocytes and tumor cells highly expressed CTLA-4. However, CTLA-4 protein expression did not predict response to treatment. We conclude that CTLA4 methylation is a predictive biomarker for response to anti-CTLA-4 immunotherapy. Keywords CTLA-4 · CTLA4 · DNA methylation · Immunotherapy · Predictive biomarker · Melanoma
Introduction Jennifer Landsberg and Dimo Dietrich are the joint senior authors in this work. * Dimo Dietrich [email protected] 1
Department of Dermatology and Allergy, University Hospital Bonn, Venusberg‑Campus, Bonn 53127, Germany
2
Department of Otolaryngology, Head and Neck Surgery, University Hospital Bonn, Venusberg‑Campus, 53127 Bonn, Germany
3
Department of Dermatology and Allergy, Technical University of Munich, Munich, Germany
4
Faculty of Medicine, Sigmund Freud University, Vienna, Austria
5
Department of Oncology, Hematology and Rheumatology, University Hospital Bonn, Bonn, Germany
6
Institute of Neuropathology, University Hospital Bonn, Bonn, Germany
7
Institute of Pathology, University Hospital Bonn, Bonn, Germany
Therapeutic monoclonal antibodies (mAbs) targeting the immune checkpoints cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1) have revolutionized the treatment of various cancers. In metastatic melanoma immune checkpoint blockade (ICB) considerably prolongates survival and even leads to durable remission in some cases [1, 2]. However, only a subgroup of patients responds to treatment due to primary resistance to ICB. This is particularly true for ipilimumab, the first in class CTLA-4-directed immune checkpoint inhibitor, which has shown efficacy in 19%
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