肿瘤细胞治疗研究
英文原题：Identification of NOXA as a pivotal regulator of resistance to CAR T-cell therapy in B-cell malignancies.
尽管嵌合抗原受体（CAR）T细胞疗法在治疗血液系统恶性肿瘤方面取得了显著成功，但耐药和复发仍会发生，而支撑这种耐药的标志物或机制仍知之甚少。
尽管嵌合抗原受体（CAR）T细胞疗法在治疗血液系统恶性肿瘤方面取得了显著成功，但耐药和复发仍会发生，而这种耐药背后的标志物或机制仍知之甚少。在此，通过无偏倚的全基因组CRISPR/Cas9筛选，我们鉴定出NOXA（一种B细胞恶性肿瘤中的B细胞淋巴瘤2（BCL2）家族蛋白）缺失是CAR T细胞治疗耐药的关键调节因子，它通过损害肿瘤细胞在体外和体内的凋亡发挥作用。值得注意的是，在复发/难治性B细胞淋巴瘤的一项串联CD19/20 CAR T临床试验中，肿瘤样本中NOXA低表达与更差的生存相关。相反，通过组蛋白去乙酰化酶（HDAC）抑制剂对NOXA表达进行药物增强，可在体外和体内显著增敏癌细胞，使其对CAR T细胞介导的清除更敏感。我们的工作揭示了NOXA在CAR T细胞治疗耐药中的必要性，并提示NOXA可作为接受CAR T细胞输注患者应答和生存的预测标志物。药物靶向NOXA可能提供一种创新治疗策略，以增强CAR T细胞治疗。
Despite the remarkable success of chimeric antigen receptor (CAR) T-cell therapy for treating hematologic malignancies, resistance and recurrence still occur, while the markers or mechanisms underlying this resistance remain poorly understood. Here, via an unbiased genome-wide CRISPR/Cas9 screening, we identified loss of NOXA, a B-cell lymphoma 2 (BCL2) family protein in B-cell malignancies, as a pivotal regulator of resistance to CAR T-cell therapy by impairing apoptosis of tumor cells both in vitro and in vivo. Notably, low NOXA expression in tumor samples was correlated with worse survival in a tandem CD19/20 CAR T clinical trial in relapsed/refractory B-cell lymphoma. In contrast, pharmacological augmentation of NOXA expression by histone deacetylase (HDAC) inhibitors dramatically sensitized cancer cells to CAR T cell-mediated clearance in vitro and in vivo. Our work revealed the essentiality of NOXA in resistance to CAR T-cell therapy and suggested NOXA as a predictive marker for response and survival in patients receiving CAR T-cell transfusions. Pharmacological targeting of NOXA might provide an innovative therapeutic strategy to enhance CAR T-cell therapy.
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