BCMA- and CST6-specific CAR T cells lyse multiple myeloma cells and suppress murine osteolytic lesions.
BCMA- and CST6-specific CAR T cells lyse multiple myeloma cells and suppress murine osteolytic lesions.
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BCMA-和cst6特异性CAR - T细胞可溶解多发性骨髓瘤细胞并抑制小鼠溶骨损伤。
DOI：
10.1172/jci171396
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发表时间：
2024-01-02
影响因子：
15.9
通讯作者：
Zhan, Fenghuang
中科院分区：
文献类型：
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作者：
Sun, Fumou;Cheng, Yan;Chen, Jin-Ran;Wanchai, Visanu;Mery, David E.;Xu, Hongwei;Gai, Dongzheng;Al Hadidi, Samer;Schinke, Carolina;Thanendrarajan, Sharmilan;Zangari, Maurizio;van Rhee, Frits;Tricot, Guido;Shaughnessy, John D., Jr.;Zhan, Fenghuang
我们以前已经证明，胱抑素E/M（CST 6），这是升高的多发性骨髓瘤（MM）缺乏溶骨性病变（OL）的患者的子集，抑制MM骨疾病通过阻断破骨细胞的分化和功能。CST 6是一种分泌型2型半胱氨酸蛋白酶抑制剂，是一种调节溶酶体半胱氨酸蛋白酶和天冬酰胺酰内肽酶legumain的半胱氨酸蛋白酶抑制剂。在这里，我们开发了B细胞成熟抗原（BCMA）CST 6嵌合抗原受体T细胞（CAR-T细胞），其裂解MM细胞并释放CST 6蛋白。我们的体外研究表明，这些CAR-T细胞抑制了抗酒石酸酸性磷酸酶阳性（TRAP+）破骨细胞的分化和形成。使用异种移植的MM小鼠，生物发光图像显示BCMA-CAR-T和BCMA-CST 6-CAR-T细胞抑制MM生长的程度相似。重建的显微计算机断层扫描图像显示，BCMA-CST 6-CAR-T细胞，而不是BCMA-CAR-T细胞，阻止了MM诱导的骨损伤并减少了破骨细胞数量。我们的研究结果提供了一种CAR-T策略，该策略直接靶向肿瘤细胞并提供骨吸收抑制剂。BCMA-CST 6-CAR-T细胞靶向多发性骨髓瘤并释放大量CST 6以抑制溶骨性病变。
We have previously demonstrated that cystatin E/M (CST6), which is elevated in a subset of patients with multiple myeloma (MM) lacking osteolytic lesions (OLs), suppresses MM bone disease by blocking osteoclast differentiation and function. CST6 is a secreted type 2 cystatin, a cysteine protease inhibitor that regulates lysosomal cysteine proteases and the asparaginyl endopeptidase legumain. Here, we developed B cell maturation antigen (BCMA) CST6 chimeric antigen receptor T cells (CAR-T cells), which lysed MM cells and released CST6 proteins. Our in vitro studies show that these CAR-T cells suppressed the differentiation and formation of tartrate-resistant acid phosphatase–positive (TRAP+) osteoclasts. Using xenografted MM mice, bioluminescence images showed that both BCMA–CAR-T and BCMA–CST6–CAR-T cells inhibited MM growth to a similar extent. Reconstructed micro–computed tomography images revealed that BCMA–CST6–CAR-T cells, but not BCMA–CAR-T cells, prevented MM-induced bone damage and decreased osteoclast numbers. Our results provide a CAR-T strategy that targets tumor cells directly and delivers an inhibitor of bone resorption. BCMA-CST6-CAR-T cells target multiple myeloma and release large amounts of CST6 to suppress osteolytic lesions.