肿瘤细胞治疗研究
英文原题：Targeting Wnt/β-catenin signaling enhances the efficacy of anti-CD38 immunotherapy in multiple myeloma.
Targeting Wnt/β-catenin signaling enhances the efficacy of anti-CD38 immunotherapy in multiple myeloma.
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这些发现表明，靶向 Wnt 信号通路可增强 daratumumab 的疗效，并为将 daratumumab 与 Wnt 信号通路抑制联合作为 MM 的治疗策略提供了强有力的依据。
既往研究表明，Wnt/β-catenin信号通路在多发性骨髓瘤（MM）中异常激活并调控MM细胞生长，而近期研究报道了Wnt与STAT3信号在多种非MM系统中的交互作用。此外，已有研究显示STAT3调控CD38的表达，而CD38是当前MM抗体治疗的关键靶点。因此，我们旨在研究抑制Wnt信号对抗CD38免疫治疗疗效的影响。
我们利用dnTCF过表达和β-catenin敲除来抑制Wnt信号通路。采用流式细胞术分析CD38的表达。使用NK92MI-CD16和脐血来源的NK细胞在细胞系及患者来源的MM中进行ADCC实验。采用异种移植小鼠模型评估体内抑制Wnt信号通路联合daratumumab的治疗效果。
我们证明，抑制Wnt信号通路会导致MM细胞系和原代MM样本中STAT3活性降低。通过抑制Wnt信号通路来抑制STAT3活性，可显著增强CD38的表达，而CD38是决定抗CD38治疗（即daratumumab）临床反应的关键因素。相应地，使用Wnt抑制剂ICG-001靶向Wnt信号通路，在体外以及体内小鼠模型中均大大增强了daratumumab的抗MM疗效。
Previous studies have shown that the Wnt/β-catenin signaling pathway is aberrantly activated in multiple myeloma (MM) and regulates the growth of MM cells, while recent studies reported crosstalk between Wnt and STAT3 signaling in various non-MM systems. In addition, it has been shown that STAT3 regulates the expression of CD38, the key target of current antibody therapies in MM. Therefore, we aimed to investigate the impact of inhibiting the Wnt signaling on the efficacy of anti-CD38 immunotherapy.
We utilized dnTCF overexpression and β-catenin knockout to inhibit the Wnt signaling. Flow cytometry was used to analyze the expression of CD38. NK92MI-CD16 and CB-derived NK cells were used to conduct ADCC in cell lines and patient-derived MM. A xenograft mouse model was used to evaluate the therapeutic efficacy of inhibiting Wnt signaling in combination with daratumumab in vivo.
We demonstrate that inhibition of Wnt signaling results in reduced STAT3 activity in both MM cell lines and primary MM samples. The suppression of STAT3 activity by Wnt signaling inhibition significantly enhances the expression of CD38, which is a crucial determinant of the clinical response to anti-CD38 treatment, viz. daratumumab. In accordance, targeting of Wnt signaling with the Wnt inhibitor ICG-001 greatly enhanced the anti-MM efficacy of daratumumab in vitro as well as in an in vivo mouse model.
These findings demonstrated that targeting Wnt signaling enhances the efficacy of daratumumab and provide a strong rationale for combining daratumumab with Wnt-signaling inhibition as a therapeutic strategy in MM.
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