CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：Single-cell atlas of the immune microenvironment reveals macrophage reprogramming and the potential dual macrophage-targeted strategy in multiple myeloma.
Single-cell atlas of the immune microenvironment reveals macrophage reprogramming and the potential dual macrophage-targeted strategy in multiple myeloma.
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肿瘤微环境（TME）在多发性骨髓瘤（MM）的疾病进展中发挥关键作用。本研究旨在呈现MM疾病进展过程中MM-TME的图谱，并探索针对TME的治疗策略。
我们对不同疾病阶段的样本进行了单细胞RNA测序（scRNAseq）。我们通过bulk RNAseq、流式细胞术（FCM）以及体外和体内功能实验验证了这些发现。
我们描绘了疾病进展过程中TME受损的特征，表现为耗竭NK细胞和CD8+ T细胞的富集以及巨噬细胞（MPs）的重编程。重编程的肿瘤相关巨噬细胞（TAMs）表现出混合表型，兼具M1和M2特征，其中两个TAM簇仅存在于MM阶段，且表现出更高的M2评分。
我们在临床队列中验证了TAMs的混合M1/M2表型，并证实了重编程TAMs的吞噬功能障碍。细胞相互作用分析鉴定了MPs与恶性浆细胞（PCs）之间两对富集的配体-受体对，包括抑制吞噬作用的SIRPA-CD47通路和重塑MPs表型的CD74-MIF（巨噬细胞抑制因子）。CD47和MIF的表达与疾病进展和不良预后相关。
我们设计了一种双MP靶向策略，将抗CD47抗体与MIF抑制剂联合使用，以激活吞噬作用并将MPs重极化至功能性表型，并在体外和体内证明了其强效抗肿瘤作用。
我们绘制了MM-TME在疾病进展过程中的变化，并揭示了TAM的重编程。同时阻断CD47和MIF的双MP靶向方法显示出强效抗肿瘤效果。
The tumour microenvironment (TME) plays a critical role in disease progression in multiple myeloma (MM).
This study aimed to present an atlas of MM-TME in disease progression and explore TME-directed therapeutic strategies.
We performed single-cell RNA sequencing (scRNAseq) in samples from different disease stages.
We validated the findings by bulk RNAseq, flow cytometry (FCM) and in vitro and in vivo functional experiments.
We delineated a compromised TME during disease progression, characterized by enrichment of exhausted NK cells and CD8 + T cells and reprogramming of macrophages (MPs). The reprogrammed tumour-associated MPs (TAMs) displayed a mixed phenotype showing both M1 and M2 features, with two TAM clusters exclusively present in the MM stage showing higher M2 scores.
We validated the mixed M1/M2 phenotype in TAMs in a clinical cohort and verified phagocytic dysfunction in reprogrammed TAMs. Cellular interaction analysis identified two enriched ligand-receptor pairs between MPs and malignant plasma cells (PCs), including the SIRPA-CD47 pathway suppressing phagocytosis and the CD74-MIF (macrophage inhibitory factor) reshaping the phenotype of MPs. The expression of CD47 and MIF correlated with disease progression and adverse outcomes.
We designed a dual-MP-targeted strategy by combining an anti-CD47 antibody and MIF inhibitor to activate phagocytosis and repolarize MP to a functional phenotype and proved its potent antitumour effect in vitro and in vivo.
We drafted alterations in MM-TME during disease progression and unravelled TAM's reprogramming. The dual MP-targeted approach blocking both CD47 and MIF showed potent antitumour effects.
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