Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Department of Hematology, Oncology and Cardiovascular Medicine, Kyushu University Hospital, Fukuoka, Japan.
Cancer Immunol Immunother. 2023 Nov;72(11):3543-3558. doi: 10.1007/s00262-023-03505-4. Epub 2023 Aug 7.
Combined immune checkpoint blockade (ICB) is effective therapy for renal cell carcinoma (RCC). However, the dynamic changes in circulating B cells induced by combined ICB have not been clarified. The present study prospectively examined 22 patients scheduled to receive ICB for unresectable or metastatic RCC between March 2018 and August 2021. Eleven patients received combined therapy with anti-PD-1 (nivolumab) and anti-CTLA-4 (ipilimumab), and the other 11 patients received nivolumab monotherapy. Comprehensive phenotypes of circulating immune cells obtained prior to and after ICB therapy were analyzed by flow cytometry. Although the proportion of naïve B cells among total B cells was significantly decreased, that of switched memory B cells was significantly increased after combined therapy. In responders, the proportion of B cells among peripheral blood mononuclear cells was significantly higher prior to ICB therapy, and the proportion of switched memory B cells among total B cells tended to increase after ICB therapy. Of note, the proportion of plasmablasts among total B cells was significantly increased after ICB therapy in patients who developed severe immune-related adverse events (irAEs), and the proportion of B cells among peripheral blood decreased significantly. Furthermore, in four of five patients who developed immune-related hypophysitis following combined therapy, anti-pituitary antibody was detected in the serum. These results suggested that immune-related hypophysitis was closely related to the increase in circulating plasmablasts. Collectively, this study suggests that combined ICB promotes the differentiation of B cell populations, which is associated with efficient tumor suppression and development of irAEs.
联合免疫检查点阻断（ICB）是肾细胞癌（RCC）的有效治疗方法。然而，联合 ICB 诱导的循环 B 细胞的动态变化尚不清楚。本研究前瞻性地检查了 2018 年 3 月至 2021 年 8 月期间计划接受 ICB 治疗不可切除或转移性 RCC 的 22 例患者。11 例患者接受抗 PD-1（nivolumab）和抗 CTLA-4（ipilimumab）联合治疗，另外 11 例患者接受 nivolumab 单药治疗。通过流式细胞术分析 ICB 治疗前后循环免疫细胞的综合表型。尽管联合治疗后总 B 细胞中幼稚 B 细胞的比例显著降低，但记忆 B 细胞的比例显著增加。在应答者中，ICB 治疗前外周血单个核细胞中 B 细胞的比例显著升高，而总 B 细胞中记忆 B 细胞的比例在 ICB 治疗后趋于升高。值得注意的是，在发生严重免疫相关不良事件（irAE）的患者中，ICB 治疗后总 B 细胞中的浆母细胞比例显著增加，外周血中的 B 细胞比例显著降低。此外，在接受联合治疗后发生免疫相关垂体炎的五名患者中的四名中，血清中检测到抗垂体抗体。这些结果表明，免疫相关垂体炎与循环浆母细胞的增加密切相关。总之，这项研究表明，联合 ICB 促进了 B 细胞群的分化，这与有效的肿瘤抑制和 irAE 的发展有关。
