Hollander Peter, Kamper Peter, Smedby Karin Ekstrom, Enblad Gunilla, Ludvigsen Maja, Mortensen Julie, Amini Rose-Marie, Hamilton-Dutoit Stephen, d'Amore Francesco, Molin Daniel, Glimelius Ingrid
Experimental and Clinical Oncology, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
Department of Hematology, Aarhus University Hospital, Aarhus, Denmark.
Blood Adv. 2017 Aug 8;1(18):1427-1439. doi: 10.1182/bloodadvances.2017006346.
Immune checkpoint inhibition targeting the programmed death receptor (PD)-1 pathway is a novel treatment approach in relapsed and refractory classical Hodgkin lymphoma (cHL). Identifying patients with a high risk of treatment failure could support the use of PD-1 inhibitors as front-line treatment. Our aim was to investigate the prognostic impact of PD-1, programmed death-ligand 1 (PD-L1), and PD-L2 in the tumor microenvironment in diagnostic biopsies of patients with cHL. Patients from Denmark and Sweden, diagnosed between 1990 and 2007 and ages 15 to 86 years, were included. Tissue microarray samples were available from 387 patients. Immunohistochemistry was used to detect PD-1, PD-L1, and PD-L2, and the proportions of positive cells were calculated. Event-free survival (EFS; time to treatment failure) and overall survival (OS) were analyzed using Cox proportional hazards regression. High proportions of both PD-1 (hazard ratio [HR], 1.77; 95% confidence interval [CI], 1.10-2.86) and PD-L1 (HR = 1.89; 95% CI, 1.08-3.30) leukocytes in the microenvironment were associated with inferior EFS in a multivariate analysis (adjusted for white blood cell count >15 × 10/L, hemoglobin <105 g/L, albumin <40 g/L, B symptoms, extranodal involvement, stage, bulky tumor, nodular sclerosis subtype, Epstein-Barr virus status, lymphocyte count <0.6 × 10/L, sex, and country). A high proportion of PD-L1 leukocytes was also associated with inferior OS in a multivariate analysis (HR, 3.46; 95% CI, 1.15-10.37). This is the first study to show a correlation after multivariate analysis between inferior outcome in cHL and a high proportion of both PD-1 and PD-L1 leukocytes in the tumor microenvironment.
靶向程序性死亡受体（PD）-1通路的免疫检查点抑制是复发难治性经典型霍奇金淋巴瘤（cHL）的一种新型治疗方法。识别具有高治疗失败风险的患者有助于将PD-1抑制剂用作一线治疗。我们的目的是研究在cHL患者诊断性活检中肿瘤微环境中PD-1、程序性死亡配体1（PD-L1）和PD-L2的预后影响。纳入了1990年至2007年间诊断的年龄在15至86岁之间的丹麦和瑞典患者。387例患者有组织微阵列样本。采用免疫组织化学检测PD-1、PD-L1和PD-L2，并计算阳性细胞比例。使用Cox比例风险回归分析无事件生存期（EFS；至治疗失败时间）和总生存期（OS）。在多变量分析中（校正白细胞计数>15×10⁹/L、血红蛋白<105 g/L、白蛋白<40 g/L、B症状、结外受累、分期、巨大肿瘤、结节硬化亚型、EB病毒状态、淋巴细胞计数<0.6×10⁹/L、性别和国家），微环境中高比例的PD-1（风险比[HR]，1.77；95%置信区间[CI]，1.10-2.86）和PD-L1白细胞（HR = 1.89；95% CI，1.08-3.30）与较差的EFS相关。在多变量分析中，高比例的PD-L1白细胞也与较差的OS相关（HR，3.46；95% CI，1.15-10.37）。这是第一项在多变量分析后显示cHL预后较差与肿瘤微环境中高比例的PD-1和PD-L1白细胞之间存在相关性的研究。
