Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
Department of Immunology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
J Dermatol. 2021 Aug;48(8):1186-1192. doi: 10.1111/1346-8138.15904. Epub 2021 Apr 22.
Anti-programmed cell death protein-1 (PD-1) antibodies have become a standard treatment for advanced melanoma. However, a predictive biomarker for assessing the efficacy of anti-PD-1 antibodies has not been identified. In cancer, CD8 T cells specific for tumor antigens undergo repeated T-cell receptor stimulation due to the persistence of cancer cells and gradually lose their ability to secrete interleukin 2 (IL-2), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ). We aimed to evaluate multi-cytokine production and immune exhaustion of peripheral CD8 T cells in melanoma patients treated with anti-PD-1 antibodies. Twenty-four melanoma patients treated with nivolumab were included. Effector cytokine production (IL-2, TNF-α, and IFN-γ) and expression of an exhaustion marker (PD-1) in patients' CD8 cells were analyzed with flow cytometry. The relationships between parameters such as the neutrophil-to-lymphocyte ratio (NLR) and clinical response to nivolumab were examined. Immunohistochemistry for programmed death-ligand 1 (PD-L1) expression in tumor cells and tumor-infiltrating lymphocytes (TILs) and analysis of their association with clinical response were performed. The clinical response rate to nivolumab was 29%. Regarding TILs, NLR, and several other parameters, no significant difference was found between responders and non-responders. The responder group showed an increase in the percentage of PD-1 CD8 /TNF-α IFN-γ or PD-1 CD8 /IFN-γ IL-2 TNF-α T cells compared to non-responders. Positivity for PD-L1 expression was significantly higher in the responder group than the non-responder group. In advanced melanoma, the percentage of multifunctional CD8 PD-1 T cells and PD-L1 expression in the tumors may be a biomarker for a good response to anti-PD-1 antibody monotherapy.
抗程序性细胞死亡蛋白 1（PD-1）抗体已成为晚期黑色素瘤的标准治疗方法。然而，尚未确定用于评估抗 PD-1 抗体疗效的预测性生物标志物。在癌症中，由于癌细胞的持续存在，针对肿瘤抗原的 CD8 T 细胞会经历反复的 T 细胞受体刺激，并且逐渐丧失分泌白细胞介素 2（IL-2）、肿瘤坏死因子-α（TNF-α）和干扰素-γ（IFN-γ）的能力。我们旨在评估接受抗 PD-1 抗体治疗的黑色素瘤患者外周血 CD8 T 细胞的多细胞因子产生和免疫耗竭情况。纳入了 24 例接受纳武单抗治疗的黑色素瘤患者。采用流式细胞术分析患者 CD8 细胞的效应细胞因子产生（IL-2、TNF-α 和 IFN-γ）和耗竭标志物（PD-1）的表达。检查了中性粒细胞与淋巴细胞比值（NLR）等参数与纳武单抗临床反应的关系。对肿瘤细胞和肿瘤浸润淋巴细胞（TIL）中的程序性死亡配体 1（PD-L1）表达进行免疫组织化学染色，并分析其与临床反应的关系。纳武单抗的临床反应率为 29%。关于 TIL、NLR 和其他几个参数，应答者和无应答者之间没有发现显著差异。与无应答者相比，应答者组 PD-1 CD8 /TNF-α IFN-γ 或 PD-1 CD8 /IFN-γ IL-2 TNF-α T 细胞的比例增加。应答者组 PD-L1 表达阳性率明显高于无应答者组。在晚期黑色素瘤中，多功能 CD8 PD-1 T 细胞的比例和肿瘤中的 PD-L1 表达可能是抗 PD-1 抗体单药治疗良好反应的生物标志物。
