CTLA4 promoter methylation predicts response and progression-free survival in stage IV melanoma treated with anti-CTLA-4 immunotherapy (ipilimumab)

• Published in: Cancer Immunology, Immunotherapy Vol. 70; no. 6; pp. 1781 - 1788
• Main Authors: Fietz, Simon, Zarbl, Romina, Niebel, Dennis, Posch, Christian, Brossart, Peter, Gielen, Gerrit H., Strieth, Sebastian, Pietsch, Torsten, Kristiansen, Glen, Bootz, Friedrich, Landsberg, Jennifer, Dietrich, Dimo
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.06.2021; Springer Nature B.V
• Subjects: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Immunological - therapeutic use; Biomarkers; Biomarkers, Tumor - genetics; Cancer Research; CTLA-4 Antigen - genetics; CTLA-4 protein; DNA Methylation; Epigenetics; Female; Follow-Up Studies; Gene Expression Regulation, Neoplastic; Humans; Immune checkpoint; Immunohistochemistry; Immunology; Immunotherapy; Ipilimumab - therapeutic use; Lymphocytes; Male; Medicine; Medicine & Public Health; Melanoma; Melanoma - drug therapy; Melanoma - mortality; Melanoma - pathology; Middle Aged; Monoclonal antibodies; Oncology; Prognosis; Promoter Regions, Genetic; Protein expression; Proteins; Research Report; Retrospective Studies; Survival Rate; Targeted cancer therapy; Tumor cells; Tumors; DNA methylation; CTLA-4; Immunotherapy; Predictive biomarker; Melanoma; CTLA4
• ISSN: 0340-7004; 1432-0851
• DOI: 10.1007/s00262-020-02777-4

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.