Department of Dermatology and Allergy, University Hospital Bonn, Venusberg-Campus, Bonn, 53127, Germany.
Department of Otolaryngology, Head and Neck Surgery, University Hospital Bonn, Venusberg-Campus, 53127, Bonn, Germany.
Cancer Immunol Immunother. 2021 Jun;70(6):1781-1788. doi: 10.1007/s00262-020-02777-4. Epub 2020 Nov 16.
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.
抗 CTLA-4 抗体可诱导肿瘤长期缓解。然而，只有少数患者有反应，因此需要开发预测性伴随生物标志物。越来越多的证据表明，表观遗传学，包括 DNA 甲基化，在免疫学和免疫检查点阻断耐药性中起主要作用。在这里，我们测试了 CTLA4 启动子甲基化和 CTLA-4 蛋白表达作为抗 CTLA-4 免疫治疗反应的预测生物标志物。我们回顾性地确定了 30 名接受单药抗 CTLA-4 免疫治疗（ipilimumab）的 IV 期黑色素瘤患者。我们使用定量甲基化特异性 PCR 和免疫组织化学来定量检测预处理样本中的 CTLA4 甲基化和蛋白表达。与缓解肿瘤相比，进展性肿瘤中 CTLA4 甲基化显著升高，与无进展生存期显著相关。一组浸润淋巴细胞和肿瘤细胞高表达 CTLA-4。然而，CTLA-4 蛋白表达不能预测治疗反应。我们得出结论，CTLA4 甲基化是抗 CTLA-4 免疫治疗反应的预测生物标志物。
