为肝细胞癌武装 GPC3 CAR-T 细胞：多少才足够，下一步是什么？
Armouring GPC3 CAR T cells for hepatocellular carcinoma: how much is enough and what comes next?
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
癌症中抗 PD-1 联合仑伐替尼治疗不同临床结局背后的细胞毒性 T 细胞与调节性 T 细胞反应对比
英文原题：Contrasting cytotoxic and regulatory T cell responses underlying distinct clinical outcomes to anti-PD-1 plus lenvatinib therapy in cancer.
查看英文原题
Contrasting cytotoxic and regulatory T cell responses underlying distinct clinical outcomes to anti-PD-1 plus lenvatinib therapy in cancer.
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中文摘要
抗PD-1联合仑伐替尼在多种癌症中显示出临床疗效，但其潜在的免疫学机制尚不清楚。在此，我们通过单细胞转录组学和T细胞受体（scTCR）克隆型分析，比较了肝细胞癌（HCC）患者联合治疗前后的T细胞。我们发现，肿瘤浸润性GZMK + CD8 + 效应/效应记忆T（Teff/Tem）细胞对联合治疗表现出良好的应答，其包括祖细胞耗竭T（Tpex）细胞以及未被充分认识且富集乙型肝炎病毒（HBV）特异性的循环Tem（cTem）细胞。进一步整合分析显示，cTem细胞与联合治疗的应答性特异性相关，而Tpex细胞则参与联合治疗和抗PD-1单药治疗的应答。值得注意的是，肿瘤中一个尚未被充分探索的KIR + CD8 + T细胞亚群以及FOXP3 + CD4 + 调节性T细胞在联合治疗后的无应答者中特异性富集。因此，我们的研究阐明了与癌症免疫治疗临床获益和耐药相关的T细胞亚群。
展开英文摘要原文
Combination of anti-PD-1 with lenvatinib showed clinical efficacy in multiple cancers, yet the underlying immunological mechanisms are unclear.
Here, we compared T cells in hepatocellular carcinoma (HCC) patients before and after combination treatment using single-cell transcriptomics and T cell receptor (scTCR) clonotype analyses.
We found that tumor-infiltrating GZMK + CD8 + effector/effector memory T (Teff/Tem) cells, showing a favorable response to combination therapy, comprise progenitor exhausted T (Tpex) cells and also unappreciated circulating Tem (cTem) cells enriched with hepatitis B virus (HBV) specificity.
Further integrated analyses revealed that cTem cells are specifically associated with responsiveness to the combination therapy, whereas Tpex cells contribute to responses in both combination therapy and anti-PD-1 monotherapy.
Notably, an underexplored KIR + CD8 + T cell subset in the tumor and FOXP3 + CD4 + regulatory T cells are specifically enriched in non-responders after the combination therapy.
Our study thus elucidated T cell subsets associated with clinical benefits and resistance in cancer immunotherapy.
论文信息
- 作者
- Guo X、Nie H、Zhang W、Li J、Ge J、Xie B、Hu W、Zhu Y
- 第一作者单位
- Shanghai Immune Therapy Institute, New Cornerstone Science Laboratory, Shanghai Jiao Tong University School of Medicine - Affiliated Renji Hospital, Shanghai 200127, China; Institute for Immunology, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China.China
- 通讯作者单位
- Shanghai Immune Therapy Institute, New Cornerstone Science Laboratory, Shanghai Jiao Tong University School of Medicine - Affiliated Renji Hospital, Shanghai 200127, China; Research Unit of Immune Regulation and Immune Diseases (2022RU001), Chinese Academy of Medical Sciences, Shanghai Jiao Tong University School of Medicine - Affiliated Renji Hospital, Shanghai 200127, China; Westlake University School of Medicine, Hangzhou, Zhejiang 310030, China. Electronic address: dongchen@westlake.edu.cn.China
- 期刊
- Cancer cell2025 Feb 10
- 原文标识
- PubMed 39889705 · DOI 10.1016/j.ccell.2025.01.001