Experimental and Clinical Oncology, Department of Immunology, Genetics and Pathology, and.
Clinical and Experimental Pathology, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
Blood Adv. 2021 Mar 23;5(6):1671-1681. doi: 10.1182/bloodadvances.2020003664.
Interleukin-6 (IL-6) can induce therapeutic resistance for several cancer agents currently used to treat classical Hodgkin lymphoma (cHL). We aimed to investigate whether the presence of IL-6+ leukocytes and IL-6+ Hodgkin-Reed-Sternberg (HRS) cells in the tumor microenvironment (TME) was associated with adverse survival outcomes, expression of other immune markers, and serum IL-6 levels. We used a contemporarily treated cohort (n = 136), with a median follow-up of 13.8 years (range, 0.59-15.9 years). We performed immunohistochemistry with an IL-6 antibody on tissue microarrays from diagnostic biopsies of cHL patients. Patients with IL-6+ leukocytes ≥1% (n = 54 of 136) had inferior event-free survival (hazard ratio [HR] = 3.58; 95% confidence interval [CI], 1.80-7.15) and overall survival (HR = 6.71; 95% CI, 2.51-17.99). The adverse survival was maintained in multivariate Cox regression and propensity score-matched analyses, adjusting for well-known poor-prognostic covariates. The presence of IL-6+ HRS cells and high serum IL-6 levels were not associated with survival. IL-6+ leukocytes correlated with increased proportions of IL-6+ HRS cells (P < .01), CD138+ plasma cells (P < .01), CD68+ macrophages (P = .02), and tryptase-positive mast cells (P < .01). IL-6+ HRS cells correlated with increased proportions of CD68+ macrophages (P = .03), programmed death-ligand 1-positive (PD-L1+) leukocytes (P = .04), and PD-L1+ HRS cells (P < .01). Serum-IL-6 lacked correlation with IL-6 expression in the TME. This is the first study highlighting the adverse prognostic impact of IL-6+ leukocytes in the TME in a cohort of contemporarily treated adult patients with cHL.
白细胞介素 6（IL-6）可诱导目前用于治疗经典霍奇金淋巴瘤（cHL）的几种癌症药物产生治疗抵抗。我们旨在研究肿瘤微环境（TME）中是否存在 IL-6+白细胞和 IL-6+Hodgkin-Reed-Sternberg（HRS）细胞与不良生存结果、其他免疫标志物的表达和血清 IL-6 水平相关。我们使用了一组同时治疗的队列（n=136），中位随访时间为 13.8 年（范围为 0.59-15.9 年）。我们使用针对 IL-6 的抗体在 cHL 患者的诊断性活检组织微阵列上进行了免疫组织化学检测。IL-6+白细胞≥1%（n=136 例中的 54 例）的患者无事件生存（风险比 [HR] = 3.58；95%置信区间 [CI]，1.80-7.15）和总生存（HR = 6.71；95%CI，2.51-17.99）均较差。多变量 Cox 回归和倾向评分匹配分析中保留了不良生存结果，调整了预后不良的已知协变量。IL-6+HRS 细胞的存在和高血清 IL-6 水平与生存无关。IL-6+白细胞与增加的 IL-6+HRS 细胞（P<0.01）、CD138+浆细胞（P<0.01）、CD68+巨噬细胞（P=0.02）和类胰蛋白酶阳性肥大细胞（P<0.01）的比例呈正相关。IL-6+HRS 细胞与 CD68+巨噬细胞（P=0.03）、程序性死亡配体 1 阳性（PD-L1+）白细胞（P=0.04）和 PD-L1+HRS 细胞（P<0.01）的比例增加呈正相关。血清 IL-6 与 TME 中的 IL-6 表达无相关性。这是第一项在一组同时接受治疗的成人 cHL 患者队列中强调 TME 中 IL-6+白细胞不良预后影响的研究。
