All-trans retinoic acid improves NSD2-mediated RARα phase separation and efficacy of anti-CD38 CAR T-cell therapy in multiple myeloma.
All-trans retinoic acid improves NSD2-mediated RARα phase separation and efficacy of anti-CD38 CAR T-cell therapy in multiple myeloma.
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DOI：
10.1136/jitc-2022-006325
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发表时间：
2023-03
影响因子：
10.9
通讯作者：
中科院分区：
文献类型：
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作者：
靶向CD 38的免疫疗法在复发性/难治性多发性骨髓瘤（MM）中表现出显著疗效。然而，CD 38抗原的丢失和CD 38阴性浆细胞的生长已经成为临床上的主要障碍。全反式维甲酸（ATRA）已被报道上调CD 38的表达，但机制和适应性遗传背景尚未探讨。通过流式细胞术评估ATRA上调MM细胞中CD 38表达的功效。免疫沉淀法分析NSD 2与RARα的相互作用，激光共聚焦显微镜观察RARα的核凝聚情况。在NOD. Cg-PrkdcscidIl 2 rgtm 1 Wjl/SzJ小鼠中建立MM的移植物模型，并通过体内荧光成像评估肿瘤负荷。我们报道了ATRA以非线性方式上调MM细胞CD 38的表达，这是t（4;14）易位依赖的，并且t（4;14）易位诱导的NSD 2与ATRA诱导的CD 38表达水平呈正相关，但与基础水平无关。在机制上，NSD 2与ATRA受体RARα相互作用，并保护其免受降解。同时，NSD 2增强RARα的核凝聚，并修饰CD 38启动子上赖氨酸36的组蛋白H3二甲基化。NSD 2的敲除可减弱MM对ATRA诱导的CD 38上调的敏感性。在体外和体内，ATRA倾向于增强抗CD 38 CAR T细胞在NSD 2 high MM细胞中的功效。这项研究阐明了ATRA调节CD 38表达的机制，并扩大了ATRA在改善MM患者抗CD 38免疫治疗方面的临床潜力。
Immunotherapies targeting CD38 have demonstrated salient efficacy in relapsed/refractory multiple myeloma (MM). However, loss of CD38 antigen and outgrowth of CD38 negative plasma cells have emerged as a major obstacle in clinics. All-trans retinoic acid (ATRA) has been reported to upregulate CD38 expression, but the mechanism and adaptive genetic background remain unexplored. The efficacy of ATRA in upregulating CD38 expression in MM cells is evaluated by flow cytometry. The interaction between NSD2 and the RARα is analyzed by immunoprecipitation, and the nuclear condensation of RARα is evaluated under laser confocal microscope. A graft model of MM is established in NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ mice, and the tumor burden is assessed by in vivo fluorescence imaging. We report that ATRA upregulates MM cells CD38 in a non-linear manner, which is t(4;14) translocation dependent, and t(4;14) translocation-induced NSD2 shows positive correlation with ATRA-induced level of, but not with basal level of CD38 expression. Mechanistically, NSD2 interacts with the ATRA receptor, RARα, and protects it from degradation. Meanwhile, NSD2 enhances the nuclear condensation of RARα and modifies the histone H3 dimethylation at lysine 36 on CD38 promoter. Knockdown of NSD2 attenuates the sensitization of MM against ATRA induced CD38 upregulation. Translationally, ATRA is prone to augment the efficacy of anti-CD38 CAR T cells in NSD2high MM cells in vitro and in vivo. This study elucidates a mechanism of ATRA in regulating CD38 expression and expands the clinical potential of ATRA in improving immunotherapies against CD38 in patients with MM.Cite Now
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