肿瘤细胞治疗研究
英文原题：Engineering anti-BCMA CAR T cells for enhancing myeloma killing efficacy via apoptosis regulation.
CAR T细胞的临床反应令人鼓舞，但原发耐药和治疗后复发使许多癌症患者无法获得持久缓解，其中癌细胞对凋亡的抵抗限制了CAR T细胞的杀伤作用可能是一个潜在原因。
嵌合抗原受体（CAR）T细胞疗法的临床应答令人鼓舞，但原发性耐药和治疗后复发阻碍许多癌症患者获得持久缓解；癌细胞抵抗凋亡并限制CAR T细胞杀伤可能是其原因之一。本研究旨在增强CAR T细胞诱导的肿瘤细胞凋亡。我们发现，过表达颗粒酶B–NOXA融合蛋白的抗B细胞成熟抗原（BCMA）CAR T细胞，在体外和体内异种移植小鼠模型中均能增强对多发性骨髓瘤（MM）细胞的杀伤。机制上，这一增强效应由NOXA定位于细胞毒颗粒介导；细胞接触后这些颗粒释放至癌细胞。在MM细胞中，NOXA作为MCL-1（抗凋亡因子）的天然配体，可有效诱导凋亡。因此，我们的数据表明，使CAR T细胞表达颗粒酶B–NOXA可增强其杀伤效力，为普遍增强CAR T细胞介导的抗癌免疫提供潜在策略。
Clinical responses with chimeric antigen receptor (CAR) T cells are encouraging, but primary resistance and relapse after therapy prevent durable remission in many patients with cancer, with apoptosis resistance in cancer cells that limits killing by CAR T cells being a potential cause. Here we aim to boost tumor cell apoptosis induced by CAR T cells and find that anti-B cell maturation antigen (BCMA) CAR T cells over-expressing a granzyme B-NOXA fusion protein show improved killing of multiple myeloma (MM) cells in vitro and in xenograft mouse models in vivo. Mechanistically, such an enhancement is mediated by localizing NOXA to cytotoxic granules that are released into cancer cells upon contact. In MM cells, inhibition of MCL-1, an anti-apoptotic factor, by its natural ligand NOXA effectively induces apoptosis. Our data thus show that endowing granzyme B-NOXA expression to CAR T cells improves their killing efficacy, thereby presenting a potential generalizable enhancement for CAR T-mediated anti-cancer immunity.
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