• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Nature >NR4A transcription factors limit CAR T cell function in solid tumours
【24h】

NR4A transcription factors limit CAR T cell function in solid tumours

机译：NR4A转录因子限制实体瘤中CAR T细胞的功能

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

T cells expressing chimeric antigen receptors (CAR T cells) targeting human CD19 (hCD19) have shown clinical efficacy against B cell malignancies(1,2). CAR T cells have been less effective against solid tumours(3-5), in part because they enter a hyporesponsive ('exhausted' or 'dysfunctional') state(6-9) triggered by chronic antigen stimulation and characterized by upregulation of inhibitory receptors and loss of effector function. To investigate the function of CAR T cells in solid tumours, we transferred hCD19-reactive CAR T cells into hCD19(+) tumour-bearing mice. CD8(+)CAR(+) tumour-infiltrating lymphocytes and CD8(+) endogenous tumour-infiltrating lymphocytes expressing the inhibitory receptors PD-1 and TIM3 exhibited similar profiles of gene expression and chromatin accessibility, associated with secondary activation of nuclear receptor transcription factors NR4A1 (also known as NUR77), NR4A2 (NURR1) and NR4A3 (NOR1) by the initiating transcription factor NFAT (nuclear factor of activated T cells)(10-12). CD8(+) T cells from humans with cancer or chronic viral infections(13-15) expressed high levels of NR4A transcription factors and displayed enrichment of NR4A-binding motifs in accessible chromatin regions. CAR T cells lacking all three NR4A transcription factors (Nr4a triple knockout) promoted tumour regression and prolonged the survival of tumour-bearing mice. Nr4a triple knockout CAR tumour-infiltrating lymphocytes displayed phenotypes and gene expression profiles characteristic of CD8(+) effector T cells, and chromatin regions uniquely accessible in Nr4a triple knockout CAR tumour-infiltrating lymphocytes compared to wild type were enriched for binding motifs for NF-kappa B and AP-1, transcription factors involved in activation of T cells. We identify NR4A transcription factors as having an important role in the cell-intrinsic program of T cell hyporesponsiveness and point to NR4A inhibition as a promising strategy for cancer immunotherapy.
机译：表达针对人CD19（hCD19）的嵌合抗原受体（CAR T细胞）的T细胞已显示出对抗B细胞恶性肿瘤的临床功效（1,2）。 CAR T细胞对实体瘤的效力较低（3-5），部分原因是它们进入由慢性抗原刺激引发的低反应性（“疲惫”或“功能失调”）状态（6-9），其特征在于抑制性受体的上调和效应器功能的丧失。为了研究CAR T细胞在实体瘤中的功能，我们将hCD19反应性CAR T细胞转移到了带有hCD19（+）的荷瘤小鼠体内。表达抑制性受体PD-1和TIM3的CD8（+）CAR（+）肿瘤浸润淋巴细胞和CD8（+）内源性肿瘤浸润淋巴细胞表现出相似的基因表达谱和染色质可及性，与核受体转录因子的二次激活相关NR4A1（也称为NUR77），NR4A2（NURR1）和NR4A3（NOR1）通过起始转录因子NFAT（活化T细胞的核因子）来表达（10-12）。来自患有癌症或慢性病毒感染的人的CD8（+）T细胞（13-15）表达高水平的NR4A转录因子，并在可进入的染色质区域显示NR4A结合基序的富集。缺少所有三个NR4A转录因子（Nr4a三联敲除）的CAR T细胞促进了肿瘤的消退并延长了荷瘤小鼠的生存期。 Nr4a三联敲除CAR肿瘤浸润淋巴细胞表现出CD8（+）效应T细胞的表型和基因表达谱，与野生型相比，Nr4a三联敲除CAR肿瘤浸润淋巴细胞独特的染色质区域富集了NF- κB和AP-1是参与T细胞活化的转录因子。我们确定NR4A转录因子在T细胞低反应性的细胞内在程序中具有重要作用，并指出NR4A抑制是一种有前景的癌症免疫疗法策略。

著录项

  • 来源
    《Nature》 |2019年第7749期|530-534|共5页
  • 作者

    Chen Joyce; Lopez-Moyado Isaac F.; Seo Hyungseok; Lio Chan-Wang J.; Hempleman Laura J.; Sekiya Takashi; Yoshimura Akihiko; Scott-Browne James P.; Rao Anjana;

  • 作者单位

    La Jolla Inst Immunol, Div Signaling & Gene Express, La Jolla, CA 92037 USA|Univ Calif San Diego, Sch Med, Biomed Sci Grad Program, La Jolla, CA 92093 USA|Univ Calif San Diego, Dept Pharmacol, La Jolla, CA 92093 USA|Sanford Consortium Regenerat Med, La Jolla, CA 92037 USA;

    La Jolla Inst Immunol, Div Signaling & Gene Express, La Jolla, CA 92037 USA|Sanford Consortium Regenerat Med, La Jolla, CA 92037 USA|Univ Calif San Diego, Bioinformat & Syst Biol Grad Program, La Jolla, CA 92093 USA;

    La Jolla Inst Immunol, Div Signaling & Gene Express, La Jolla, CA 92037 USA;

    La Jolla Inst Immunol, Div Signaling & Gene Express, La Jolla, CA 92037 USA;

    La Jolla Inst Immunol, Div Signaling & Gene Express, La Jolla, CA 92037 USA;

    Natl Ctr Global Hlth & Med, Dept Immune Regulat, Ichikawa, Chiba, Japan;

    Keio Univ, Sch Med, Dept Microbiol & Immunol, Tokyo, Japan;

    La Jolla Inst Immunol, Div Signaling & Gene Express, La Jolla, CA 92037 USA|Sanford Consortium Regenerat Med, La Jolla, CA 92037 USA|Natl Jewish Hlth, Dept Biomed Res, Denver, CO 80206 USA;

    La Jolla Inst Immunol, Div Signaling & Gene Express, La Jolla, CA 92037 USA|Univ Calif San Diego, Dept Pharmacol, La Jolla, CA 92093 USA|Sanford Consortium Regenerat Med, La Jolla, CA 92037 USA|Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号