CAR-T（CAR-T）细胞疗法在非肿瘤性疾病中的应用
Chimeric antigen receptor T (CAR-T) cell therapy in non-oncological diseases.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
靶向 PARP11 规避免疫抑制并改善实体瘤 CAR-T 疗法
英文原题：Targeting PARP11 to avert immunosuppression and improve CAR T therapy in solid tumors.
查看英文原题
Targeting PARP11 to avert immunosuppression and improve CAR T therapy in solid tumors.
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中文摘要
免疫抑制性肿瘤微环境（TME）有助于实体瘤逃避免疫监视并产生治疗耐药。我们发现，调节性 T 细胞和腺苷等 TME 因素会下调 CD8⁺ 细胞毒性 T 淋巴细胞（CTL）上的 I 型干扰素受体 IFNAR1。这些变化依赖聚 ADP-核糖聚合酶 11（PARP11）；PARP11 在肿瘤内 CTL 中被诱导表达，是 TME 免疫抑制的关键调节因子。敲除 PARP11 可防止 IFNAR1 丢失，增强 CTL 杀伤肿瘤的活性，并以 IFNAR1 依赖的方式抑制肿瘤生长。因此，遗传或药理学失活 PARP11 可增强CAR-T 细胞的治疗获益。经工程化改造以失活 PARP11 的嵌合抗原受体 CTL 对实体瘤显示出更优疗效。这些发现揭示 PARP11 在免疫抑制性 TME 中的作用，并提供了靶向该通路以优化免疫疗法的概念验证。
展开英文摘要原文
Evasion of antitumor immunity and resistance to therapies in solid tumors are aided by an immunosuppressive tumor microenvironment (TME).
We found that TME factors, such as regulatory T cells and adenosine, downregulated type I interferon receptor IFNAR1 on CD8 + cytotoxic T lymphocytes (CTLs). These events relied upon poly-ADP ribose polymerase-11 (PARP11), which was induced in intratumoral CTLs and acted as a key regulator of the immunosuppressive TME.
Ablation of PARP11 prevented loss of IFNAR1, increased CTL tumoricidal activity and inhibited tumor growth in an IFNAR1-dependent manner. Accordingly, genetic or pharmacologic inactivation of PARP11 augmented the therapeutic benefits of chimeric antigen receptor T cells. Chimeric antigen receptor CTLs engineered to inactivate PARP11 demonstrated a superior efficacy against solid tumors.
These findings highlight the role of PARP11 in the immunosuppressive TME and provide a proof of principle for targeting this pathway to optimize immune therapies.
论文信息
- 作者
- Zhang H、Yu P、Tomar VS、Chen X、Atherton MJ、Lu Z、Zhang HG、Li S
- 第一作者单位
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA.United States
- 通讯作者单位
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA. syfuchs@upenn.edu.United States
- 文献类型
- 美国 NIH 资助研究 · 非美国政府资助研究
- 期刊
- Nature cancer2022 Jul
- 原文标识
- PubMed 35637402 · DOI 10.1038/s43018-022-00383-0
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