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BACKGROUND

Combination therapy with radioembolization (yttrium-90)-resin microspheres) followed by nivolumab has shown a promising response rate of 30.6% in a Phase II trial (CA209-678) for advanced hepatocellular carcinoma (HCC); however, the response mechanisms and relevant biomarkers remain unknown.

METHODS

By collecting both pretreatment and on-treatment samples, we performed multimodal profiling of tissue and blood samples and investigated molecular changes associated with favorable responses in 33 patients from the trial.

RESULTS

We found that higher tumor mutation burden, mutations and higher expression of interferon gamma pathways occurred more frequently in responders. Meanwhile, non-responders tended to be enriched for a novel Asian-specific transcriptomic subtype (Kaya_P2) with a high frequency of chromosome 16 deletions and upregulated cell cycle pathways. Strikingly, unlike other cancer types, we did not observe any association between T-cell populations and treatment response, but tumors from responders had a higher proportion of CXCL9/CXCR3 macrophages. Moreover, biomarkers discovered in previous immunotherapy trials were not predictive in the current cohort, suggesting a distinctive molecular landscape associated with differential responses to the combination therapy.

CONCLUSIONS

This study unraveled extensive molecular changes underlying distinctive responses to the novel treatment and pinpointed new directions for harnessing combination therapy in patients with advanced HCC.

背景

在一项针对晚期肝细胞癌（HCC）的 II 期试验（CA209-678）中，钇-90-树脂微球联合免疫检查点抑制剂nivolumab 的联合治疗显示出 30.6%的有希望的缓解率；然而，反应机制和相关的生物标志物仍然未知。

方法

通过收集治疗前和治疗中的样本，我们对来自该试验的 33 名患者的组织和血液样本进行了多模式分析，并研究了与有利反应相关的分子变化。

结果

我们发现，在应答者中，更高的肿瘤突变负担、突变和更高的干扰素 γ 途径表达更频繁地发生。同时，无应答者倾向于富集一种新型的亚洲特异性转录亚型（Kaya_P2），其染色体 16 缺失频率较高，细胞周期途径上调。引人注目的是，与其他癌症类型不同，我们没有观察到 T 细胞群体与治疗反应之间的任何关联，但应答者的肿瘤中具有更高比例的 CXCL9/CXCR3 巨噬细胞。此外，在当前队列中，先前免疫治疗试验中发现的生物标志物没有预测性，这表明与对联合治疗的不同反应相关的独特分子景观。