Department of Phase 1 Trials Center, Harbin Medical University Cancer Hospital, Harbin, People's Republic of China.
School of Basic Medical Sciences, Harbin Medical University, Harbin, People's Republic of China.
J Immunother Cancer. 2024 Nov 24;12(11):e010534. doi: 10.1136/jitc-2024-010534.
Despite the success of immune checkpoint inhibitor (ICI)-based combination therapies in hepatocellular carcinoma (HCC), its effectiveness remains confined to a subset of patients. The development of reliable, predictive markers is important for accurate patient stratification and further mechanistic understanding of therapy response.
We comprehensively analyzed paired single-cell RNA transcriptome and T-cell repertoire profiles from 14 HCC ascites samples, collected from 7 patients before and after treatment with the combination of sintilimab (anti-PD-1) and bevacizumab (anti-VEGF).
We identify a widespread convergence on interferon (IFN) signaling across various immune cell lineages in treatment-responsive patients with HCC, indicating a common transcriptional state transition in the immune microenvironment linked to immunotherapy response in HCC. Strong IFN signaling marks CD8 T cells with larger clonal expansion and enhanced cytotoxicity, macrophages toward M1-like polarization and strong T-cell recruitment ability, dendritic cells with increased antigen presentation capacity, as well as highly cytotoxic natural killer cells and activated B cells. By translating our finding to cohorts of patients with HCC, we demonstrate the specificity of IFN-signaling in the prognosis of patients with HCC and its ability to predict immunotherapy response.
This study provides a unique single-cell resource with clonal and longitudinal resolution during ICI therapy and reveals IFN signaling as a biomarker of immunotherapy response in HCC, suggesting a beneficial effect by combining IFN inducers with ICIs for patients with HCC.
尽管免疫检查点抑制剂 (ICI) 联合治疗在肝细胞癌 (HCC) 中取得了成功,但其疗效仍然局限于一部分患者。开发可靠的、预测性的标志物对于准确的患者分层和进一步了解治疗反应的机制非常重要。
我们全面分析了 7 名 HCC 患者在接受信迪利单抗(anti-PD-1)和贝伐珠单抗(anti-VEGF)联合治疗前后的 14 份 HCC 腹水样本的单细胞 RNA 转录组和 T 细胞受体库的配对分析。
我们发现,在对 HCC 免疫治疗有反应的患者中,各种免疫细胞谱系中干扰素 (IFN) 信号广泛趋同,这表明免疫微环境中的共同转录状态转变与 HCC 的免疫治疗反应有关。强烈的 IFN 信号标志着 CD8 T 细胞具有更大的克隆扩增和增强的细胞毒性,巨噬细胞向 M1 样极化和强大的 T 细胞募集能力,树突状细胞具有增强的抗原呈递能力,以及高度细胞毒性的自然杀伤细胞和活化的 B 细胞。通过将我们的发现转化为 HCC 患者的队列中,我们证明了 IFN 信号在 HCC 患者预后中的特异性及其预测免疫治疗反应的能力。
这项研究提供了一个独特的单细胞资源,具有克隆和纵向分辨率,在 ICI 治疗期间揭示了 IFN 信号作为 HCC 免疫治疗反应的生物标志物,提示联合 IFN 诱导剂和 ICI 对 HCC 患者有益。