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CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
DNAJB1-PRKACA 融合新抗原引发罕见的内源性 T 细胞反应，可增强纤维板层型肝癌的细胞治疗
英文原题：DNAJB1-PRKACA fusion neoantigens elicit rare endogenous T cell responses that potentiate cell therapy for fibrolamellar carcinoma.
查看英文原题
DNAJB1-PRKACA fusion neoantigens elicit rare endogenous T cell responses that potentiate cell therapy for fibrolamellar carcinoma.
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中文摘要
纤维板层型肝癌（FLC）是一种死亡率高且治疗选择有限的肝脏肿瘤。FLC中一个有前景的治疗脆弱性是其驱动突变，即一种保守的DNAJB1-PRKACA基因融合，可能成为免疫治疗的理想靶向新抗原。在本研究中，我们旨在明确FLC患者对该融合的内源性CD8 T细胞反应，并评估融合特异性T细胞受体（TCR）用于细胞免疫治疗的可行性。我们观察到融合特异性CD8 T细胞较为罕见，且FLC患者的TCR repertoire缺乏与强效抗原特异性反应特征相符的大型相关TCR序列簇，这可能解释了为何内源性免疫反应不足以清除FLC肿瘤。尽管如此，我们定义了两种具有功能的融合特异性TCR，其中一种在体内具有强效抗肿瘤活性。总之，我们的结果提供了对人类新抗原特异性repertoire碎片化本质的见解，并指出了FLC成功免疫治疗临床开发的方向。
展开英文摘要原文
Fibrolamellar carcinoma (FLC) is a liver tumor with a high mortality burden and few treatment options. A promising therapeutic vulnerability in FLC is its driver mutation, a conserved DNAJB1-PRKACA gene fusion that could be an ideal target neoantigen for immunotherapy. In this study, we aim to define endogenous CD8 T cell responses to this fusion in FLC patients and evaluate fusion-specific T cell receptors (TCRs) for use in cellular immunotherapies.
We observe that fusion-specific CD8 T cells are rare and that FLC patient TCR repertoires lack large clusters of related TCR sequences characteristic of potent antigen-specific responses, potentially explaining why endogenous immune responses are insufficient to clear FLC tumors. Nevertheless, we define two functional fusion-specific TCRs, one of which has strong anti-tumor activity in vivo.
Together, our results provide insights into the fragmented nature of neoantigen-specific repertoires in humans and indicate routes for clinical development of successful immunotherapies for FLC.
论文信息
- 作者
- Kirk AM、Crawford JC、Chou CH、Guy C、Pandey K、Kozlik T、Shah RK、Chung S
- 第一作者单位
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.United States
- 通讯作者单位
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address: paul.thomas@stjude.org.United States
- 期刊
- Cell reports. Medicine2024 Mar 19
- 原文标识
- PubMed 38508137 · DOI 10.1016/j.xcrm.2024.101469
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