肿瘤细胞治疗研究
英文原题：Multiple Myeloma Cells Resistant to T-cell Therapies Exhibit a CD45+ Immunoevasive Phenotype.
Multiple Myeloma Cells Resistant to T-cell Therapies Exhibit a CD45+ Immunoevasive Phenotype.
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这些发现提示，T 细胞重定向治疗（TCRT）驱动一种以 CD45 上调和免疫检查点激活为特征的免疫逃逸表型，支持将 TCRT 与检查点抑制剂联合以克服复发/难治性多发性骨髓瘤的耐药。
多发性骨髓瘤是一种浆细胞恶性肿瘤，即便近年来治疗取得进展（如靶向B细胞成熟抗原[BCMA]的嵌合抗原受体[CAR]T细胞及双特异性T细胞衔接抗体[TCE]），多数患者仍无法治愈。为更好理解治疗耐药，我们检查了这些治疗后残存的多发性骨髓瘤细胞，并持续观察到CD45上调，这是耐药程序的一部分。研究对骨髓样本进行离体处理，采用BCMA CAR-T 细胞、TCE抗体（elranatamab、SAR442257）或活化T细胞治疗，并通过流式细胞术分析。研究还利用伊德卡布他基因维克仑赛（抗BCMA CAR-T 治疗）前后的患者样本及播散性多发性骨髓瘤小鼠体内模型，验证CD45上调。残存的多发性骨髓瘤细胞表面可见局灶性CD45斑块。机制研究提示分泌型HSP70可能参与其中；整体RNA测序则发现LAG-3、IFN信号及PD-L1表达增加。这些发现提示，T细胞重定向治疗（TCRT）可促使肿瘤形成免疫逃逸表型，其特征为CD45上调及免疫检查点活化；支持将TCRT与检查点抑制剂联合，以克服复发/难治性多发性骨髓瘤的耐药。
Multiple myeloma is a plasma cell malignancy that is mostly incurable, even with recent advances in treatment such as B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR) T cells and bispecific T cell-engaging (TCE) antibodies. To better understand this treatment resistance, we examined multiple myeloma cells that persisted after these treatments and consistently observed CD45 upregulation as part of a resistance program. Bone marrow samples were treated ex vivo with BCMA CAR T cells, TCE antibodies (elranatamab, SAR442257), or activated T cells and analyzed via flow cytometry. CD45 upregulation was validated in patient samples before and after idecabtagene vicleucel therapy (anti-BCMA CAR T-cell therapy) and using an in vivo mouse model of disseminated multiple myeloma. Persisting multiple myeloma cells exhibited focal CD45 surface patches. Mechanistic studies implicated secreted HSP70, whereas bulk RNA sequencing revealed increased LAG-3, IFN signaling, and PD-L1 expression. These findings suggest that T cell-redirecting therapy (TCRT) drives an immunoevasive phenotype defined by CD45 upregulation and immune checkpoint activation, supporting combination strategies of TCRT with checkpoint inhibitors to overcome resistance in relapsed/refractory multiple myeloma.
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