Department of Pulmonology, University Hospital Zurich, Raemistrasse 100, 8091, Zurich, Switzerland.
Department of Immunology, University Hospital Zurich, Gloriastrasse 23, 8091, Zurich, Switzerland.
J Cancer Res Clin Oncol. 2022 Jul;148(7):1711-1720. doi: 10.1007/s00432-021-03750-z. Epub 2021 Aug 4.
Immune-checkpoint inhibitors (ICI) present a new treatment for malignancies by boosting the immune system. This has led to a variety of immune-related adverse events, including ICI-associated pneumonitis (ICIaP). Diagnosis thereof is often challenging, and its pathogenesis has not yet been fully understood. The aim of this cross-sectional case-control study was to investigate cytokines in serum and bronchoalveolar lavage fluid (BALF) expressed in patients with ICIaP compared to controls consisting of healthy individuals, patients with lung cancer and patients with interstitial lung diseases (ILD) other than ICIaP.
From January 2018 until June 2019, 401 adult patients with various lung diseases were prospectively enrolled in a BALF- and serum biobank, called BALOTHEK. Of these, 12 patients were diagnosed with ICIaP (Pembrolizumab, Ipilimumab, or both, and Durvalumab) serving as case group. Subjects with one of three diagnosis groups from BALOTHEK, including lung cancer, ILD other than ICIaP, and healthy individuals, served as matched controls. The following 11 cytokines were simultaneously analyzed in BALF and serum of each study participant: interferon gamma, tumor necrosis factor alpha, interleukin (IL) 1b, IL-2, IL-4, IL-5, IL-6, IL-8, IL-12p70, IL-13 and IL-17A. This study was approved by the local ethic review committee (BASEC-ID 2017-02,307 and 2018-01,724).
Absolute number and percentage of lymphocytes in BALF of patients with ICIaP were significantly higher compared to control groups. For the investigated cytokines in BALF, a significant increase of IL-6 level was shown for patients with ICIaP compared to control groups (p = 0.031, adjusted for multiple comparisons).
Cytokine profile assessed in BALF shows promising potential for facilitating diagnosis and understanding of pathophysiology of ICIaP. IL-6 may not only contribute to better understanding of pathophysiology but also herald therapeutic implications for Tocilizumab.
免疫检查点抑制剂（ICI）通过增强免疫系统为恶性肿瘤提供了新的治疗方法。这导致了各种免疫相关的不良反应，包括 ICI 相关性肺炎（ICIaP）。其诊断通常具有挑战性，其发病机制尚未完全了解。本横断面病例对照研究的目的是调查与健康个体、肺癌患者和 ICIaP 以外的间质性肺疾病（ILD）患者相比，ICIaP 患者血清和支气管肺泡灌洗液（BALF）中表达的细胞因子。
从 2018 年 1 月到 2019 年 6 月，401 名患有各种肺部疾病的成年患者前瞻性地入组了一个 BALF 和血清生物库，称为 BALOTHEK。其中，12 名患者被诊断为 ICIaP（Pembrolizumab、Ipilimumab 或两者联合，以及 Durvalumab），作为病例组。BALOTHEK 中的三种诊断组之一的受试者，包括肺癌、ICIaP 以外的ILD 和健康个体，作为匹配对照组。同时分析每个研究参与者的 BALF 和血清中的以下 11 种细胞因子：干扰素γ、肿瘤坏死因子-α、白细胞介素（IL）1b、IL-2、IL-4、IL-5、IL-6、IL-8、IL-12p70、IL-13 和 IL-17A。本研究得到了当地伦理审查委员会的批准（BASEC-ID 2017-02，307 和 2018-01，724）。
与对照组相比，ICIaP 患者 BALF 中的淋巴细胞绝对数和百分比明显更高。对于 BALF 中研究的细胞因子，与对照组相比，ICIaP 患者的 IL-6 水平显著升高（p = 0.031，经多重比较调整）。
BALF 中评估的细胞因子谱对于促进 ICIaP 的诊断和理解发病机制具有有希望的潜力。IL-6 不仅可能有助于更好地理解发病机制，而且预示着对托珠单抗的治疗意义。
