肿瘤细胞治疗研究
英文原题：Single-cell multiomic dissection of response and resistance to chimeric antigen receptor T cells against BCMA in relapsed multiple myeloma.
目前尚缺乏可预测复发/难治性多发性骨髓瘤中对嵌合抗原受体（CAR）T 细胞应答和耐药的标志物。
目前尚缺乏可预测复发/难治性多发性骨髓瘤患者对嵌合抗原受体（CAR）T 细胞应答或耐药的标志物。本研究对患者接受已获批的靶向 B 细胞成熟抗原（BCMA）CAR-T 治疗前后的外周血和骨髓单个核细胞进行单细胞多组学分析，以识别与耐药和早期复发相关的标志。在白细胞单采时，应答者和非应答者之间已存在差异。非应答者呈现免疫抑制性微环境，表现为表达免疫检查点分子 CD39 的单核细胞增多，CD8+ T 细胞和自然杀伤（NK）细胞功能受抑。对 CAR-T 细胞的分析发现，与低度或中度扩增克隆相比，高度扩增克隆具有细胞毒性并呈耗竭表型。研究还发现 CAR-T 细胞上的潜在免疫治疗靶点，如 PD-1，或可用于改善其功能和持久性。本研究提供了免疫抑制性微环境导致多发性骨髓瘤 CAR-T 治疗耐药的证据。
Markers that predict response and resistance to chimeric antigen receptor (CAR) T cells in relapsed/refractory multiple myeloma are currently missing. We subjected mononuclear cells isolated from peripheral blood and bone marrow before and after the application of approved B cell maturation antigen-directed CAR T cells to single-cell multiomic analyses to identify markers associated with resistance and early relapse. Differences between responders and nonresponders were identified at the time of leukapheresis. Nonresponders showed an immunosuppressive microenvironment characterized by increased numbers of monocytes expressing the immune checkpoint molecule CD39 and suppressed CD8 + T cell and natural killer cell function. Analysis of CAR T cells showed cytotoxic and exhausted phenotypes in hyperexpanded clones compared to low/intermediate expanded clones. We identified potential immunotherapy targets on CAR T cells, like PD1, to improve their functionality and durability. Our work provides evidence that an immunosuppressive microenvironment causes resistance to CAR T cell therapies in multiple myeloma.
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