Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Maidashi, Higashi-ku, Fukuoka, Japan.
Department of Medicine and Comprehensive Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Maidashi, Higashi-ku, Fukuoka, Japan.
Int Immunol. 2020 Jul 28;32(8):547-557. doi: 10.1093/intimm/dxaa022.
Immune-checkpoint inhibitors (ICIs) have improved clinical outcomes and are becoming a standard treatment for many cancer types. However, these drugs also induce immune-related adverse events, among which interstitial lung disease (ILD) is potentially fatal. The underlying mechanism of ILD induction by ICIs is largely unknown. With the use of flow cytometry, we determined the expression levels of the immune-checkpoint proteins PD-1, TIM-3, TIGIT, LAG-3 and PD-L1 in T cells of bronchoalveolar lavage fluid (BALF) from patients with ICI-related ILD and compared them with those for patients with sarcoidosis or with ILD related to connective tissue disease or cytotoxic drug use. The proportions of CD8+ T cells positive for both PD-1 and TIM-3 or for TIGIT in BALF were significantly higher for ICI-related ILD patients than for those with other types of ILD. A prominent increase in the proportion of PD-1+PD-L1+ cells among CD8+ T cells was also apparent in BALF of a patient with a fatal case of ICI-related ILD, and the proportion of such cells was positively correlated with the grade of ICI-related ILD. Our data reveal the immune-checkpoint profiles of T cells in ICI-related ILD and may provide mechanistic insight into the development of this adverse event.
免疫检查点抑制剂 (ICIs) 改善了临床结果,并且成为许多癌症类型的标准治疗方法。然而,这些药物也会引起免疫相关的不良反应,其中间质性肺病 (ILD) 可能是致命的。ICI 诱导 ILD 的潜在机制在很大程度上尚不清楚。我们使用流式细胞术,测定了来自 ICI 相关 ILD 患者支气管肺泡灌洗液 (BALF) 中 T 细胞的免疫检查点蛋白 PD-1、TIM-3、TIGIT、LAG-3 和 PD-L1 的表达水平,并将其与结节病患者、与结缔组织病或细胞毒性药物使用相关的 ILD 患者进行了比较。与其他类型的 ILD 患者相比,ICI 相关 ILD 患者 BALF 中 CD8+ T 细胞同时表达 PD-1 和 TIM-3 或 TIGIT 的比例显著更高。在一名致命性 ICI 相关 ILD 患者的 BALF 中,PD-1+PD-L1+细胞在 CD8+ T 细胞中的比例也明显增加,并且这些细胞的比例与 ICI 相关 ILD 的严重程度呈正相关。我们的数据揭示了 ICI 相关 ILD 中 T 细胞的免疫检查点特征,并可能为这种不良反应的发生提供机制上的见解。