细胞因子作为生物标志物对接受体外光化学疗法的白血病皮肤 T 细胞淋巴瘤患者的固有免疫应答的增强作用。
Boost of innate immunity cytokines as biomarkers of response to extracorporeal photopheresis in patients with leukaemic cutaneous T-cell lymphoma.
机构信息
Department of Dermatology, Lausanne University Hospital (CHUV), and Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.
Departments of Dermatology.
出版信息
Br J Dermatol. 2023 Oct 25;189(5):603-611. doi: 10.1093/bjd/ljad220.
BACKGROUND
Extracorporeal photopheresis (ECP) has emerged as a systemic first-line immunomodulatory therapy in leukaemic cutaneous T-cell lymphoma (L-CTCL) and is now beginning to be utilized in other T-cell-mediated diseases. Although ECP has been used for nearly 30 years, its mechanisms of action are not sufficiently understood, and biomarkers for response are scarce.
OBJECTIVES
We aimed to investigate the immunomodulatory effects of ECP on cytokine secretion patterns in patients with L-CTCL, to help elucidate its mechanism of action.
METHODS
A total of 25 patients with L-CTCL and 15 healthy donors (HDs) were enrolled in this retrospective cohort study. Concentrations of 22 cytokines were simultaneously quantified by using multiplex bead-based immunoassays. Neoplastic cells in patients' blood were evaluated by flow cytometry.
RESULTS
Firstly, we observed a distinct cytokine profile pattern difference between L-CTCLs and HDs. There was a significant loss of tumour necrosis factor (TNF)-α, and significant increase of interleukins (IL)-9, IL-12 and IL-13 in the sera of patients with L-CTCL compared with HDs. Secondly, patients with L-CTCL who received ECP were classified as treatment responders and nonresponders according to the quantitative reduction of malignant burden in their blood. We evaluated cytokine levels in culture supernatants from patients' peripheral blood mononuclear cells (PBMCs) at baseline and 27 weeks after ECP initiation. Strikingly, PBMCs purified from ECP responders released statistically higher concentrations of innate immune cytokines IL-1α, IL-1β, granulocyte-macrophage colony-stimulating factor (GM-CSF) and TNF-α in comparison with ECP nonresponders. In parallel, responders showed clearance of erythema, reduction of malignant clonal T cells in the blood, and a potent boost of relevant innate immune cytokines in individual patients with L-CTCL.
CONCLUSIONS
Taken together, our results demonstrate that ECP stimulates the innate immune network, and facilitates redirection of the tumour-biased immunosuppressive microenvironment towards proactive antitumour immune responses. The alterations of IL-1α, IL-1β, GM-CSF and TNF-α can be used as biomarkers of response to ECP in patients with L-CTCL.
背景
体外光分离术（ECP）已成为白血病皮肤 T 细胞淋巴瘤（L-CTCL）的一线系统性免疫调节治疗方法，目前开始应用于其他 T 细胞介导的疾病。尽管 ECP 已经使用了近 30 年，但它的作用机制尚未得到充分理解，并且反应的生物标志物也很少。
目的
我们旨在研究 ECP 对 L-CTCL 患者细胞因子分泌模式的免疫调节作用，以帮助阐明其作用机制。
方法
本回顾性队列研究共纳入 25 例 L-CTCL 患者和 15 名健康供体（HD）。采用多指标 bead 免疫分析方法同时定量 22 种细胞因子。通过流式细胞术评估患者血液中的肿瘤细胞。
结果
首先，我们观察到 L-CTCL 患者与 HD 患者之间存在明显的细胞因子谱模式差异。与 HD 相比，L-CTCL 患者血清中肿瘤坏死因子（TNF）-α显著降低，白细胞介素（IL）-9、IL-12 和 IL-13 显著升高。其次，根据血液中恶性负担的定量减少，将接受 ECP 的 L-CTCL 患者分为治疗反应者和非反应者。我们评估了患者外周血单个核细胞（PBMC）培养上清液中细胞因子水平，分别在 ECP 开始前和 27 周后。令人惊讶的是，与 ECP 无反应者相比，从 ECP 反应者中纯化的 PBMC 释放出统计学上更高浓度的固有免疫细胞因子 IL-1α、IL-1β、粒细胞-巨噬细胞集落刺激因子（GM-CSF）和 TNF-α。同时，反应者表现为红斑消退、血液中恶性克隆 T 细胞减少，并在个别 L-CTCL 患者中有效增强相关固有免疫细胞因子。
结论
综上所述，我们的研究结果表明，ECP 刺激固有免疫网络，并促进肿瘤偏向的免疫抑制微环境向主动抗肿瘤免疫反应的转变。IL-1α、IL-1β、GM-CSF 和 TNF-α 的变化可作为 L-CTCL 患者对 ECP 反应的生物标志物。
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