Objectives Yttrium-90 (Y90)-radioembolisation (RE) significantly regresses locally advanced hepatocellular carcinoma and delays disease progression. The current study is designed to deeply interrogate the immunological impact of Y90-RE, which elicits a sustained therapeutic response. Design Time-of-flight mass cytometry and next-generation sequencing (NGS) were used to analyse the immune landscapes of tumour-infiltrating leucocytes (TILs), tumour tissues and peripheral blood mononuclear cells (PBMCs) at different time points before and after Y90-RE. Results TILs isolated after Y90-RE exhibited signs of local immune activation: higher expression of granzyme B (GB) and infiltration of CD8+ T cells, CD56+ NK cells and CD8+ CD56+ NKT cells. NGS confirmed the upregulation of genes involved in innate and adaptive immune activation in Y90-RE-treated tumours. Chemotactic pathways involving CCL5 and CXCL16 correlated with the recruitment of activated GB+CD8+ T cells to the Y90-RE-treated tumours. When comparing PBMCs before and after Y90-RE, we observed an increase in tumour necrosis factor-α on both the CD8+ and CD4+ T cells as well as an increase in percentage of antigen-presenting cells after Y90-RE, implying a systemic immune activation. Interestingly, a high percentage of PD-1+/Tim-3+CD8+ T cells coexpressing the homing receptors CCR5 and CXCR6 denoted Y90-RE responders. A prediction model was also built to identify sustained responders to Y90-RE based on the immune profiles from pretreatment PBMCs. Conclusion High-dimensional analysis of tumour and systemic immune landscapes identified local and systemic immune activation that corresponded to the sustained response to Y90-RE. Potential biomarkers associated with a positive clinical response were identified and a prediction model was built to identify sustained responders prior to treatment.

中文翻译：

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免疫激活是肝细胞癌中钇 90 放射栓塞持续临床反应的基础

目标 Yttrium-90 (Y90)-radioembolisation (RE) 显着消退局部晚期肝细胞癌并延缓疾病进展。当前的研究旨在深入探究 Y90-RE 的免疫学影响，从而引发持续的治疗反应。设计 使用飞行时间质谱流式细胞术和二代测序 (NGS) 分析肿瘤浸润白细胞 (TIL)、肿瘤组织和外周血单核细胞 (PBMC) 在 Y90 前后不同时间点的免疫图谱-关于。结果 Y90-RE 后分离的 TIL 表现出局部免疫激活的迹象：颗粒酶 B (GB) 的更高表达和 CD8+ T 细胞、CD56+ NK 细胞和 CD8+ CD56+ NKT 细胞的浸润。NGS 证实了在 Y90-RE 处理的肿瘤中参与先天性和适应性免疫激活的基因上调。涉及 CCL5 和 CXCL16 的趋化途径与激活的 GB+CD8+ T 细胞募集到 Y90-RE 处理的肿瘤相关。在比较 Y90-RE 前后的 PBMC 时，我们观察到 CD8+ 和 CD4+ T 细胞上的肿瘤坏死因子-α 增加，以及 Y90-RE 后抗原呈递细胞百分比增加，这意味着系统免疫激活. 有趣的是，共表达归巢受体 CCR5 和 CXCR6 的高百分比 PD-1+/Tim-3+CD8+ T 细胞表示 Y90-RE 应答者。还建立了一个预测模型，以根据预处理 PBMC 的免疫概况识别对 Y90-RE 的持续反应者。结论 肿瘤和全身免疫景观的高维分析确定了与对 Y90-RE 的持续反应相对应的局部和全身免疫激活。确定了与积极临床反应相关的潜在生物标志物，并建立了预测模型以在治疗前确定持续反应者。