肿瘤细胞治疗研究
英文原题：Targeting CD74 may mitigate immune-escape features and enhance BCMA CAR-T activity in preclinical models of relapsed/refractory multiple myeloma.
CD74 参与 R/R MM 的免疫逃逸和 CAR-T 耐药。
背景：靶向 B 细胞成熟抗原（BCMA）的嵌合抗原受体（CAR）T 细胞疗法已为复发/难治性多发性骨髓瘤（R/R MM）带来显著临床获益。然而，免疫逃逸和治疗耐药仍是重大挑战，残留疾病的分子特征尚未完全阐明。 方法：研究对 BCMA CAR-T 治疗前后的配对骨髓样本进行单细胞 RNA 测序（scRNA-seq），以表征治疗后存活的骨髓瘤细胞。功能验证包括体外共培养、基因扰动和体内异种移植模型。通过抗 CD74 单克隆抗体 milatuzumab 抑制 CD74。 结果：研究发现残留骨髓瘤亚群中 CD74 和巨噬细胞迁移抑制因子（MIF）表达上调。暴露于 BCMA CAR-T 细胞会诱导 MM 细胞表达 CD74 并分泌 MIF。CD74 过表达增强细胞增殖和抗凋亡能力；敲低 CD74 则损害细胞活力。在体内异种移植模型中，阻断 CD74 与 BCMA CAR-T 联用可协同降低肿瘤负荷、延长生存并抑制 CD74 表达。MIF-CD74/CD44 轴可能帮助残留疾病在免疫压力下持续存在。 结论：CD74 参与 R/R MM 的免疫逃逸和 CAR-T 耐药。靶向 CD74 可增强 BCMA CAR-T 疗效，可能成为克服复发/难治性骨髓瘤耐药的可行联合策略。试验注册号：ChiCTR2000040368。
BACKGROUND: B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T-cell therapy has demonstrated substantial clinical benefit in relapsed/refractory multiple myeloma (R/R MM). Nonetheless, immune escape and therapeutic resistance remain major challenges, and the molecular features of residual disease have not been fully elucidated. METHODS: Single-cell RNA sequencing (scRNA-seq) was applied to paired bone marrow samples collected before and after BCMA CAR-T treatment to characterize treatment-persistent myeloma cells. Functional validation involved in vitro co-culture assays, genetic perturbation, and in vivo xenograft modeling. CD74 inhibition was performed using the anti-CD74 monoclonal antibody milatuzumab. RESULTS: Residual myeloma subpopulations were identified with upregulated CD74 and migration inhibitory factor (MIF) expression. Exposure to BCMA CAR-T cells induced CD74 expression and MIF secretion in MM cells. CD74 overexpression enhanced proliferation and apoptosis resistance, while CD74 knockdown impaired cell viability. In an in vivo xenograft model, CD74 blockade synergized with BCMA CAR-T cells to reduce tumor burden, prolong survival, and suppress CD74 expression. The MIF-CD74/CD44 axis was implicated in sustaining residual disease under immune pressure. CONCLUSIONS: CD74 contributes to immune escape and CAR-T resistance in R/R MM. Therapeutic targeting of CD74 enhances BCMA CAR-T efficacy and may offer a viable combinatorial strategy to overcome resistance in R/R myeloma. TRIAL REGISTRATION NUMBER: ChiCTR2000040368.
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