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.
CAR-T（CAR-T）细胞在血液系统恶性肿瘤中的应用推动了这种免疫治疗形式的显著进展。
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
CD8(+) T 细胞中的 RNA 聚合酶 II 暂停因子 NELF 促进抗肿瘤免疫
英文原题：RNA polymerase II pausing factor NELF in CD8(+) T cells promotes antitumor immunity.
查看英文原题
RNA polymerase II pausing factor NELF in CD8(+) T cells promotes antitumor immunity.
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中文摘要
T细胞因子1（TCF1）是记忆性和干性CD8+ T细胞功能所必需的。TCF1如何与其他转录因子协同调控转录仍不清楚。在此，我们表明负延伸因子（NELF），一种RNA聚合酶II（Pol II）暂停因子，在T细胞对癌症的应答中与TCF1协同作用。在小鼠成熟T淋巴细胞中敲除编码NELFB亚基的Nelfb，会损害对原发性肿瘤攻击和肿瘤抗原介导疫苗接种的免疫应答。Nelfb敲除导致更多耗竭和减少的记忆T细胞群体，而其异位表达则增强抗肿瘤免疫和CAR-T 细胞免疫疗法的疗效。在机制上，NELF与TCF1相关联，并优先被招募到TCF1靶基因的增强子和启动子上。Nelfb消融减少了这些TCF1相关位点上的Pol II暂停和染色质可及性。因此，我们的发现表明NELF在抗肿瘤免疫中具有重要且限速的功能。
展开英文摘要原文
T cell factor 1 (TCF1) is required for memory and stem-like CD8 + T cell functions. How TCF1 partners with other transcription factors to regulate transcription remains unclear.
Here we show that negative elongation factor (NELF), an RNA polymerase II (Pol II) pausing factor, cooperates with TCF1 in T cell responses to cancer. Deletion of mouse Nelfb, which encodes the NELFB subunit, in mature T lymphocytes impairs immune responses to both primary tumor challenge and tumor antigen-mediated vaccination. Nelfb deletion causes more exhausted and reduced memory T cell populations, whereas its ectopic expression boosts antitumor immunity and efficacy of chimeric antigen receptor T-cell immunotherapy.
Mechanistically, NELF is associated with TCF1 and recruited preferentially to the enhancers and promoters of TCF1 target genes. Nelfb ablation reduces Pol II pausing and chromatin accessibility at these TCF1-associated loci.
Our findings thus suggest an important and rate-limiting function of NELF in anti-tumor immunity.
论文信息
- 作者
- Wu B、Zhang X、Chiang HC、Pan H、Yuan B、Mitra P、Qi L、Simonyan H
- 第一作者单位
- Department of Biochemistry & Molecular Medicine, The George Washington University, Washington, DC, 20037, USA.United States
- 通讯作者单位
- Department of Biochemistry & Molecular Medicine, The George Washington University, Washington, DC, 20037, USA. rli69@gwu.edu.United States
- 文献类型
- 美国政府（非公共卫生署）资助研究 · 美国 NIH 资助研究 · 非美国政府资助研究
- 期刊
- Nature communications2022 Apr 20
- 原文标识
- PubMed 35444206 · DOI 10.1038/s41467-022-29869-2
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