CRISPR-based screens uncover determinants of immunotherapy response in multiple myeloma.
CRISPR-based screens uncover determinants of immunotherapy response in multiple myeloma.
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DOI：
10.1182/bloodadvances.2019001346
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发表时间：
2020-06
期刊：
影响因子：
7.5
通讯作者：
Poornima Ramkumar;Anthony B. Abarientos;Ruilin Tian;M. Seyler;J. Leong;Merissa Chen;P. Choudhry;Torsten Hechler;N. Shah;S. Wong;T. Martin;J. Wolf;Kole T. Roybal;A. Pahl;J. Taunton;A. Wiita;M. Kampmann
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文献类型：
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作者：
Poornima Ramkumar;Anthony B. Abarientos;Ruilin Tian;M. Seyler;J. Leong;Merissa Chen;P. Choudhry;Torsten Hechler;N. Shah;S. Wong;T. Martin;J. Wolf;Kole T. Roybal;A. Pahl;J. Taunton;A. Wiita;M. Kampmann
癌细胞通常通过抗原表达的丧失而对免疫疗法产生抗性。增加癌细胞表面靶抗原水平的组合治疗有可能恢复免疫治疗的功效。在这里，我们使用我们的基于CRISPR干扰和CRISPR激活的功能基因组学平台来系统地鉴定控制多发性骨髓瘤免疫治疗抗原B细胞成熟抗原（BCMA）的细胞表面表达的途径。我们发现HDAC 7和Sec 61复合物的药理学抑制增加了细胞表面BCMA，包括在原代患者细胞中。药理学Sec 61抑制增强靶向BCMA的抗体-药物缀合物的抗骨髓瘤功效。CRISPR干扰嵌合抗原受体T细胞（CAR-T细胞）共培养筛选使我们能够鉴定控制骨髓瘤细胞对靶向BCMA的CAR-T细胞的应答的抗原依赖性和抗原非依赖性机制。因此，我们的研究显示了CRISPR筛选的潜力，以揭示控制癌细胞对免疫疗法的反应的机制，并提出潜在的联合疗法。
Cancer cells commonly develop resistance to immunotherapy by loss of antigen expression. Combinatorial treatments that increase levels of the target antigen on the surface of cancer cells have the potential to restore efficacy to immunotherapy. Here, we use our CRISPR interference- and CRISPR activation-based functional genomics platform to systematically identify pathways controlling cell surface expression of the multiple myeloma immunotherapy antigen B-cell maturation antigen (BCMA). We discovered that pharmacologic inhibition of HDAC7 and the Sec61 complex increased cell surface BCMA, including in primary patient cells. Pharmacologic Sec61 inhibition enhanced the antimyeloma efficacy of a BCMA-targeted antibody-drug conjugate. A CRISPR interference chimeric antigen receptor T cells (CAR-T cells) coculture screen enabled us to identify both antigen-dependent and antigen-independent mechanisms controlling response of myeloma cells to BCMA-targeted CAR-T cells. Thus, our study shows the potential of CRISPR screens to uncover mechanisms controlling response of cancer cells to immunotherapy and to suggest potential combination therapies.