PDF(Pubmed)
Abstract：
Multiple myeloma (MM) is a plasma cell disease with a preferential bone marrow (BM) tropism. Enforced expression of tissue-specific chemokine receptors has been shown to successfully guide adoptively-transferred CAR NK cells towards the malignant milieu in solid cancers, but also to BM-resident AML and MM. For redirection towards BM-associated chemokine CXCL12, we armored BCMA CAR-NK-92 as well as primary NK cells with ectopic expression of either wildtype CXCR4 or a gain-of-function mutant CXCR4R334X. Our data showed that BCMA CAR-NK-92 and -primary NK cells equipped with CXCR4 gained an improved ability to migrate towards CXCL12 in vitro. Beyond its classical role coordinating chemotaxis, CXCR4 has been shown to participate in T cell co-stimulation, which prompted us to examine the functionality of CXCR4-cotransduced BCMA-CAR NK cells. Ectopic CXCR4 expression enhanced the cytotoxic capacity of BCMA CAR-NK cells, as evidenced by the ability to eliminate BCMA-expressing target cell lines and primary MM cells in vitro and through accelerated cytolytic granule release. We show that CXCR4 co-modification prolonged BCMA CAR surface deposition, augmented ZAP-70 recruitment following CAR-engagement, and accelerated distal signal transduction kinetics. BCMA CAR sensitivity towards antigen was enhanced by virtue of an enhanced ZAP-70 recruitment to the immunological synapse, revealing an increased propensity of CARs to become triggered upon CXCR4 overexpression. Unexpectedly, co-stimulation via CXCR4 occurred in the absence of CXCL12 ligand-stimulation. Collectively, our findings imply that co-modification of CAR-NK cells with tissue-relevant chemokine receptors affect adoptive NK cell therapy beyond improved trafficking and retention within tumor sites.
摘要：
多发性骨髓瘤（MM）是一种浆细胞疾病，具有优先的骨髓（BM）嗜性。组织特异性趋化因子受体的强制表达已被证明可以成功地将过继转移的CARNK细胞引导到实体癌的恶性环境中。也包括BM居民AML和MM。为了重定向到BM相关的趋化因子CXCL12，我们用野生型CXCR4或功能获得突变体CXCR4R334X的异位表达对BCMACAR-NK-92以及原代NK细胞进行了装甲。我们的数据显示,配备有CXCR4的BCMCAR-NK-92和原代NK细胞在体外获得了向CXCL12迁移的改善的能力。除了协调趋化性的经典作用之外，CXCR4已被证明参与T细胞共刺激，这促使我们检查CXCR4共转导的BCMA-CARNK细胞的功能。异位CXCR4表达增强BCMACAR-NK细胞的细胞毒性能力，如通过体外消除表达BCMA的靶细胞系和原代MM细胞的能力以及通过加速的溶细胞颗粒释放所证明的。我们表明CXCR4共修饰延长了BCMACAR表面沉积，在汽车参与之后，增强了ZAP-70的招募，和加速远端信号转导动力学。BCMACAR对抗原的敏感性通过增强的ZAP-70募集到免疫突触而增强，揭示了在CXCR4过表达时CAR被触发的倾向增加。出乎意料的是,在不存在CXCL12配体刺激的情况下发生通过CXCR4的共刺激。总的来说，我们的研究结果暗示,CAR-NK细胞与组织相关趋化因子受体的共修饰对过继性NK细胞治疗的影响超出了在肿瘤部位内的转运和滞留改善.
