NR4A transcription factors limit CAR T cell function in solid tumours
NR4A transcription factors limit CAR T cell function in solid tumours
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DOI：
10.1038/s41586-019-0985-x
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发表时间：
2019-03-28
期刊：
影响因子：
64.8
通讯作者：
Rao, Anjana
中科院分区：
文献类型：
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作者：
Chen, Joyce;Lopez-Moyado, Isaac F.;Rao, Anjana
表达靶向人CD 19（hCD 19）的嵌合抗原受体（CAR T细胞）的T细胞已显示出对B细胞恶性肿瘤的临床疗效（1，2）。CAR T细胞对实体瘤的有效性较低（3-5），部分原因是它们进入由慢性抗原刺激触发的低应答（“耗尽”或“功能障碍”）状态（6-9），其特征在于抑制性受体的上调和效应子功能的丧失。为了研究CAR T细胞在实体瘤中的功能，我们将hCD 19反应性CAR T细胞转移到hCD 19（+）荷瘤小鼠中。表达抑制性受体PD-1和TIM 3的CD 8（+）CAR（+）肿瘤浸润淋巴细胞和CD 8（+）内源性肿瘤浸润淋巴细胞表现出相似的基因表达和染色质可及性特征，与核受体转录因子NR 4A 1的次级活化相关（也称为NR 477）、NR 4A 2（NR 4 R1）和NR 4A 3（NOR 1）通过起始转录因子NFAT（活化T细胞的核因子）（10-12）。来自患有癌症或慢性病毒感染的人的CD 8（+）T细胞（13-15）表达高水平的NR 4A转录因子，并且在可接近的染色质区域中显示NR 4A结合基序的富集。缺乏所有三种NR 4A转录因子（Nr 4a三重敲除）的CAR T细胞促进了肿瘤消退并延长了荷瘤小鼠的生存期。Nr 4a三重敲除CAR肿瘤浸润性淋巴细胞显示出CD 8（+）效应T细胞特征性的表型和基因表达谱，并且与野生型相比，Nr 4a三重敲除CAR肿瘤浸润性淋巴细胞中唯一可接近的染色质区域富集NF-κ B和AP-1（参与T细胞活化的转录因子）的结合基序。我们确定NR 4A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NR 4A抑制是癌症免疫治疗的一种有前途的策略。
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.