在体外淋巴细胞扩增过程中抑制 G9a/GLP 可增强工程化 T 细胞对肝细胞癌的体内细胞毒性

英文原题：G9a/GLP inhibition during ex vivo lymphocyte expansion increases in vivo cytotoxicity of engineered T cells against hepatocellular carcinoma.

PubMed 2023/02/02（内容时间） Nat Commun Q1 · IF 18.1（JCR 2025）

肝细胞癌地区：亚太其他

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研究概要

工程化T细胞瞬时表达肿瘤靶向受体是一种有吸引力的工程化T细胞疗法形式，因为它们没有插入突变或长期不良副作用的风险。

中文摘要

工程化T细胞瞬时表达肿瘤靶向受体是一种有吸引力的工程化T细胞治疗形式，因为它们不携带插入突变或长期不良副作用的风险。然而，通常需要多轮治疗，增加了患者的不适和费用。为了缓解这一问题，我们试图通过筛选一组靶向表观遗传调控因子的小分子对T细胞细胞毒性的影响，来提高瞬时工程化T细胞的抗肿瘤活性。使用靶向肝细胞癌的工程化T细胞模型，我们发现在体外模型和原位小鼠模型中，短期抑制G9a/GLP可增加T细胞抗肿瘤活性。抑制G9a/GLP可增加颗粒酶表达，而不引起终末T细胞分化或耗竭，并导致参与促炎通路、T细胞活化和细胞毒性的基因和蛋白质表达发生特异性变化。

展开英文摘要原文

Engineered T cells transiently expressing tumor-targeting receptors are an attractive form of engineered T cell therapy as they carry no risk of insertional mutagenesis or long-term adverse side-effects. However, multiple rounds of treatment are often required, increasing patient discomfort and cost. To mitigate this, we sought to improve the antitumor activity of transient engineered T cells by screening a panel of small molecules targeting epigenetic regulators for their effect on T cell cytotoxicity. Using a model for engineered T cells targetting hepatocellular carcinoma, we find that short-term inhibition of G9a/GLP increases T cell antitumor activity in in vitro models and an orthotopic mouse model. G9a/GLP inhibition increases granzyme expression without terminal T cell differentiation or exhaustion and results in specific changes in expression of genes and proteins involved in pro-inflammatory pathways, T cell activation and cytotoxicity.

论文信息

作者: Lam MSY、Reales-Calderon JA、Ow JR、Aw JJY、Tan D、Vijayakumar R、Ceccarello E、Tabaglio T
第一作者单位: Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), 138673, Singapore, Singapore.Singapore
通讯作者单位: Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), 138673, Singapore, Singapore. andreap@imcb.a-star.edu.sg.Singapore
文献类型: 非美国政府资助研究
期刊: Nature communications2023 Feb 2

原文标识: PubMed 36732506　·　DOI 10.1038/s41467-023-36160-5

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