探讨基于 PBMC 的功能测定在鉴定抗 PD-1 免疫治疗预测性生物标志物中的潜在应用。

Exploring the Potential Use of a PBMC-Based Functional Assay to Identify Predictive Biomarkers for Anti-PD-1 Immunotherapy.

机构信息

Office of Biotechnology Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA.

Office of Vaccines Research & Review, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA.

出版信息

Int J Mol Sci. 2020 Nov 27;21(23):9023. doi: 10.3390/ijms21239023.

The absence of reliable, robust, and non-invasive biomarkers for anti- Programmed cell death protein 1 (PD-1) immunotherapy is an urgent unmet medical need for the treatment of cancer patients. No predictive biomarkers have been established based on the direct assessment of T cell functions, the primary mechanism of action of anti-PD-1 therapy. In this study, we established a model system to test T cell functions modulated by Nivolumab using anti-CD3 monoclonal antibody (mAb)-stimulated peripheral blood mononuclear cells (PBMCs), and characterized T cell functions primarily based on the knowledge gained from retrospective observations of patients treated with anti-PD-1 immunotherapy. During a comprehensive cytokine profile assessment to identify potential biomarkers, we found that Nivolumab increases expression of T helper type 1 (Th1) associated cytokines such as interferon-γ (IFN-γ) and interleukin-2 (IL-2) in a subset of donors. Furthermore, Nivolumab increases production of Th2, Th9, and Th17 associated cytokines, as well as many proinflammatory cytokines such as IL-6 in a subset of donors. Conversely, Nivolumab treatment has no impact on T cell proliferation, expression of CD25, CD69, or Granzyme B, and only modestly increases in the expansion of regulatory T cells. Our results suggest that assessment of cytokine production using a simple PBMC-based T cell functional assay could be used as a potential predictive marker for anti-PD-1 immunotherapy.

目前缺乏可靠、稳健且非侵入性的抗程序性细胞死亡蛋白 1（PD-1）免疫治疗生物标志物，这是癌症患者治疗的一个亟待满足的医学需求。尚未基于对 T 细胞功能的直接评估（抗 PD-1 治疗的主要作用机制）建立任何预测性生物标志物。在这项研究中，我们建立了一个模型系统，用于测试使用抗 CD3 单克隆抗体（mAb）刺激外周血单核细胞（PBMC）时nivolumab 调节的 T 细胞功能，并主要基于对接受抗 PD-1 免疫治疗的患者的回顾性观察所获得的知识来描述 T 细胞功能。在进行全面的细胞因子谱评估以鉴定潜在的生物标志物时，我们发现nivolumab 在一部分供体中增加了 T 辅助细胞 1（Th1）相关细胞因子的表达，如干扰素-γ（IFN-γ）和白细胞介素-2（IL-2）。此外，nivolumab 在一部分供体中增加了 Th2、Th9 和 Th17 相关细胞因子以及许多促炎细胞因子（如 IL-6）的产生。相反，nivolumab 治疗对 T 细胞增殖、CD25、CD69 或颗粒酶 B 的表达没有影响，仅适度增加调节性 T 细胞的扩增。我们的研究结果表明，使用基于 PBMC 的简单 T 细胞功能测定评估细胞因子产生情况，可能成为抗 PD-1 免疫治疗的潜在预测标志物。