Institute of Translational Research, Ochsner Health System, New Orleans, Louisiana.
Interventional Radiology, Ochsner Health System, New Orleans, Louisiana.
Cancer Res Commun. 2024 Aug 1;4(8):2163-2173. doi: 10.1158/2767-9764.CRC-24-0228.
Yttrium-90 (90Y) transarterial radioembolization can safely and effectively treat hepatocellular carcinoma (HCC). Clinical trials combining 90Y with immunotherapy are aimed at improving treatment response rates. The impact of transient 90Y-induced lymphopenia on T-cell homeostasis and functional dynamics is unknown. Paired blood specimens were collected prior to first-cycle 90Y and at imaging follow-up in patients with HCC Barcelona Clinic Liver Cancer stages A-B. Flow cytometry and T-cell receptor (TCR) sequencing were used to monitor changes in T-cell subsets and TCR repertoire following 90Y. Objective response (OR) rates were determined using modified RECIST and defined as either OR or nonobjective response. Time-to-progression (TTP) was defined as progression to Barcelona Clinic Liver Cancer stage C within 6 months following 90Y. 90Y induced shifts in both CD4+ (P = 0.049) and CD8+ (P < 0.001) toward an effector memory T-cell response independent of treatment response rate. Nonresponders to 90Y were characterized by a sustained elevation in both naïve CD4+ cells (P = 0.019) and programmed cell death protein 1 expression in CD8+ cells (P = 0.003). Paired analysis of the TCR repertoire revealed a variable induction of neoantigen clonotypes and expansion of existing clonotypes independent of 90Y response. In patients with an OR, changes in TCR clonality did not influence TTP. However, polyclonal profiles in patients without an OR were associated with shorter TTP (P = 0.005; HR, 10.8) and 75% disease progression rates 6 months following treatment. 90Y induces a population shift from central to effector memory accompanied by neoantigen T-cell responses independent of treatment response rate. Monoclonal shifts in the post-90Y T-cell repertoire had superior overall TTP and improved TTP in patients with a first-cycle nonobjective response.
90Y can safely treat HCC; however, it causes transient lymphopenia. In this article, 90Y stimulates a peripheral effector memory response independent of initial treatment response. TCR sequencing revealed that polyclonal profiles in patients without an OR to treatment were associated with rapid progression rates 6 months after 90Y.
钇-90（90Y）经动脉放射性栓塞治疗可以安全有效地治疗肝细胞癌（HCC）。将 90Y 与免疫疗法相结合的临床试验旨在提高治疗反应率。暂时的 90Y 诱导的淋巴细胞减少对 T 细胞动态平衡和功能动态的影响尚不清楚。在巴塞罗那临床肝癌分期 A-B 的 HCC 患者中，在第一周期 90Y 前和影像学随访时采集配对血样。使用流式细胞术和 T 细胞受体（TCR）测序监测 90Y 后 T 细胞亚群和 TCR 库的变化。使用改良的 RECIST 确定客观反应（OR）率，并定义为 OR 或非客观反应。无进展生存期（TTP）定义为 90Y 后 6 个月内进展为巴塞罗那临床肝癌 C 期。90Y 诱导 CD4+（P=0.049）和 CD8+（P<0.001）向效应记忆 T 细胞反应的转变，与治疗反应率无关。90Y 无反应者的特征是幼稚 CD4+细胞持续升高（P=0.019）和 CD8+细胞程序性细胞死亡蛋白 1 表达升高（P=0.003）。TCR 库的配对分析显示，新抗原克隆型的诱导和现有克隆型的扩增是可变的，与 90Y 反应无关。在 OR 患者中，TCR 克隆性的变化并不影响 TTP。然而，无 OR 患者的多克隆谱与较短的 TTP（P=0.005；HR，10.8）和治疗后 6 个月 75%的疾病进展率相关。90Y 诱导从中枢到效应记忆的群体转移，伴有新抗原 T 细胞反应，与治疗反应率无关。90Y 后 T 细胞库中的单克隆转移具有更好的总体 TTP，并改善了首次非客观反应治疗患者的 TTP。
90Y 可以安全治疗 HCC；然而，它会导致短暂的淋巴细胞减少症。在本文中，90Y 刺激外周效应记忆反应，与初始治疗反应无关。TCR 测序显示，无治疗反应患者的多克隆谱与 90Y 后 6 个月快速进展率相关。
