Background & Aims

The combination of atezolizumab and bevacizumab (atezo+bev) is the current standard of care for advanced hepatocellular carcinoma (HCC), providing a median overall survival (OS) of 19.2 months. Here, we aim to uncover the underlying cellular processes driving clinical benefit versus resistance to atezo+bev.

Methods

We harnessed the power of single-cell RNA sequencing in advanced HCC to derive gene expression signatures recapitulating 21 cell phenotypes. These signatures were applied to 422 RNA-sequencing samples of advanced HCC patients treated with atezo+bev (n=317) versus atezolizumab (n=47) or sorafenib (n=58) as comparators.

Results

We unveiled two distinct patterns of response to atezo+bev. First, an immune-mediated response characterized by the combined presence of CD8+ T effector cells and pro-inflammatory CXCL10+ macrophages, representing an immune rich microenvironment. Second, a non-immune, angiogenesis-related response distinguishable by a reduced expression of the VEGF co-receptor neuropilin-1 (NRP1), a biomarker that specifically predicts improved OS upon atezo+bev vs sorafenib (p = 0.039). Primary resistance was associated with an enrichment of immunosuppressive myeloid populations, namely CD14+ monocytes and TREM2+ macrophages, and Notch pathway activation. Based on these mechanistic insights we define "Immune-competent" and "Angiogenesis-driven" molecular subgroups, each associated with a significantly longer OS with atezo+bev versus sorafenib (p of interaction = 0.027), and a “Resistant” subset.

Conclusion

Our study unveils two distinct molecular subsets of clinical benefit to atezolizumab plus bevacizumab in advanced HCC (“Immune-competent” and “Angiogenesis-driven”) as well as the main traits of primary resistance to this therapy, thus providing a molecular framework to stratify patients based on clinical outcome and guiding potential strategies to overcome resistance.

中文翻译：

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单细胞 RNA seq 衍生的特征定义了晚期肝细胞癌对 atezolizumab + 贝伐珠单抗的反应模式

 背景和目标

atezolizumab 和贝伐珠单抗 （atezo+bev） 的组合是目前晚期肝细胞癌 （HCC） 的治疗标准，中位总生存期 （OS） 为 19.2 个月。在这里，我们旨在揭示驱动临床获益与 atezo + bev 耐药性的潜在细胞过程。

 方法

我们利用晚期 HCC 中单细胞 RNA 测序的力量来获得概括 21 种细胞表型的基因表达特征。这些特征应用于接受 atezo + bev （n=317） 与 atezolizumab （n=47） 或索拉非尼 （n=58） 治疗的晚期 HCC 患者的 422 个 RNA 测序样本作为对照。

 结果

我们揭示了对 atezo + bev 的两种不同的反应模式。首先，免疫介导的反应以 CD8+ T 效应细胞和促炎性 CXCL10+ 巨噬细胞的组合存在为特征，代表免疫丰富的微环境。其次，非免疫性、血管生成相关反应可通过 VEGF 辅助受体神经纤毛蛋白-1 （NRP1） 的表达降低来区分，NRP1 是一种生物标志物，可特异性预测 atezo + bev 与索拉非尼相比 OS 改善 （p = 0.039）。原发性耐药与免疫抑制性髓系细胞群（即 CD14 + 单核细胞和 TREM2 + 巨噬细胞）的富集以及 Notch 通路激活有关。基于这些机制见解，我们定义了“免疫能力”和“血管生成驱动”分子亚群，每个分子亚群都与 atezo + bev 与索拉非尼相比明显更长的 OS 相关（相互作用 p = 0.027），以及“耐药”亚群。

 结论

我们的研究揭示了 atezolizumab 联合贝伐珠单抗在晚期 HCC 中临床益处的两个不同的分子亚群（“免疫功能正常”和“血管生成驱动”）以及对这种疗法的原发性耐药的主要特征，从而提供了一个分子框架，可以根据临床结果对患者进行分层，并指导克服耐药性的潜在策略。