Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore 169856, Singapore.
Division of Medical Oncology, National Cancer Centre Singapore, Singapore 169610, Singapore.
J Hepatol. 2022 Sep;77(3):683-694. doi: 10.1016/j.jhep.2022.03.039. Epub 2022 Apr 15.
BACKGROUND & AIMS: While immune checkpoint blockade (ICB) has shown promise in patients with hepatocellular carcinoma (HCC), it is associated with modest response rates and immune-related adverse events (irAEs) are common. In this study, we aimed to decipher immune trajectories and mechanisms of response and/or irAEs in patients with HCC receiving anti-programmed cell death 1 (anti-PD-1) therapy.
Pre- and on-treatment peripheral blood samples (n = 60) obtained from 32 patients with HCC (Singapore cohort) were analysed by cytometry by time-of-flight and single-cell RNA sequencing, with flow cytometric validation in an independent Korean cohort (n = 29). Mechanistic validation was conducted by bulk RNA sequencing of 20 pre- and on-treatment tumour biopsies and using a murine HCC model treated with different immunotherapeutic combinations.
Single-cell analyses identified CXCR3CD8 effector memory T (T) cells and CD11c antigen-presenting cells (APC) as associated with response (p = 0.0004 and 0.0255, respectively), progression-free survival (p = 0.00079 and 0.0015, respectively), and irAEs (p = 0.0034 and 0.0125, respectively) in anti-PD-1-treated patients with HCC. Type-1 conventional dendritic cells were identified as the specific APC associated with response, while 2 immunosuppressive CD14 myeloid clusters were linked to reduced irAEs. Further analyses of CXCR3CD8 T cells showed cell-cell interactions specific to response vs. irAEs, from which the anti-PD-1 and anti-TNFR2 combination was harnessed to uncouple these effects, resulting in enhanced response without increased irAEs in a murine HCC model.
This study identifies early predictors of clinical response to anti-PD-1 ICB in patients with HCC and offers mechanistic insights into the immune trajectories of these immune subsets at the interface between response and toxicity. We also propose a new combination immunotherapy for HCC to enhance response without exacerbating irAEs.
NCT03695952.
Response rates to immune checkpoint blockade (ICB) treatment in hepatocellular carcinoma (HCC) remain modest and adverse events are common. Herein, we identified early predictors of response and gained an in-depth understanding of the immunological mechanisms behind response and adverse events in patients with HCC treated with ICB. We also proposed a new combination immunotherapy for HCC that enhances response without exacerbating adverse events.
免疫检查点阻断（ICB）在肝细胞癌（HCC）患者中显示出疗效，但反应率较低，且常发生免疫相关不良事件（irAEs）。本研究旨在解析接受抗程序性细胞死亡蛋白 1（抗 PD-1）治疗的 HCC 患者的免疫轨迹和反应及/或 irAEs 的机制。
对 32 例 HCC 患者（新加坡队列）的 60 例治疗前和治疗时的外周血样本（n=60）进行了流式细胞术时间飞行和单细胞 RNA 测序分析，并在独立的韩国队列（n=29）中进行了流式细胞术验证。通过对 20 例治疗前和治疗时的肿瘤活检进行批量 RNA 测序和使用不同免疫治疗组合治疗的小鼠 HCC 模型进行了机制验证。
单细胞分析确定 CXCR3CD8 效应记忆 T（T）细胞和 CD11c 抗原呈递细胞（APC）与反应（p=0.0004 和 0.0255）、无进展生存期（p=0.00079 和 0.0015）和 irAEs（p=0.0034 和 0.0125）相关。在接受抗 PD-1 治疗的 HCC 患者中，I 型传统树突状细胞被确定为与反应相关的特定 APC，而 2 个具有免疫抑制作用的 CD14 髓样簇与减少 irAEs 相关。对 CXCR3CD8 T 细胞的进一步分析表明，从反应与 irAEs 之间的细胞-细胞相互作用中，可以分离出抗 PD-1 和抗 TNFR2 联合使用，以分离这些效应，从而在小鼠 HCC 模型中增强反应而不增加 irAEs。
本研究确定了 HCC 患者抗 PD-1 ICB 临床反应的早期预测因子，并为这些免疫亚群在反应与毒性之间的免疫轨迹提供了机制见解。我们还提出了一种新的 HCC 联合免疫疗法，可增强反应而不加重 irAEs。
NCT03695952。
免疫检查点阻断（ICB）治疗肝细胞癌（HCC）的反应率仍然较低，且不良事件常见。本研究确定了 HCC 患者对 ICB 治疗反应的早期预测因子，并深入了解了接受 ICB 治疗的 HCC 患者的反应和不良事件背后的免疫机制。我们还提出了一种新的 HCC 联合免疫疗法，可增强反应而不加重不良事件。
