免疫检查点抑制增强硼替佐米和 STING 激动剂联合在 Vk*MYC 临床前模型中的抗骨髓瘤活性。
Immune checkpoint inhibition improves antimyeloma activity of bortezomib and STING agonist combination in Vk*MYC preclinical model.
机构信息
Laboratory of Experimental Medicine, Centre of New Technologies, University of Warsaw, Banacha, 2C, 02-097, Warsaw, Poland.
Central Laboratory, University Clinical Center of Medical University of Warsaw, Banacha 1A, 02-097, Warsaw, Poland.
出版信息
Clin Exp Med. 2023 Sep;23(5):1563-1572. doi: 10.1007/s10238-022-00878-1. Epub 2022 Aug 31.
UNLABELLED
Multiple myeloma (MM), a hematological malignancy of plasma cells, has remained incurable despite the development of novel therapies that improve patients' outcome. Recent evidence indicates that the stimulator of interferon genes (STING) pathway may represent a novel target for induction of antitumor immune response in multiple myeloma. Here, we investigated antitumor effects of STING agonist with bortezomib with or without checkpoint inhibitor in the treatment of MM.
METHODS
STING expression in bone marrow plasma cells of 58 MM patients was examined by immunohistochemical staining. The effectiveness of the proposed therapy was evaluated in vivo in a syngeneic transplantable mouse model of MM (Vĸ*MYC) in immunocompetent mice. Flow cytometry was used to assess tumor burden and investigate activation of immune response against MM. ELISA was performed to measure serum inflammatory cytokines concentrations upon treatment.
RESULTS
Combining a STING agonist [2'3'-cGAM(PS)] with bortezomib significantly decreased tumor burden and improved the survival of treated mice compared to either of the compounds used alone. The combination treatment led to secretion of pro-inflammatory cytokines and increased the percentage of neutrophils, activated dendritic cells and T cells in the tumor microenvironment. However, it resulted also in increased expression of PD-L1 on the surface of the immune cells. Addition of anti-PD1 antibody further potentiated the therapeutic effects.
CONCLUSIONS
Our findings indicate high antimyeloma efficacy of the three-drug regimen comprising bortezomib, STING agonist, and a checkpoint inhibitor.
未标记
多发性骨髓瘤（MM）是一种浆细胞血液恶性肿瘤，尽管新型疗法的发展改善了患者的预后，但仍然无法治愈。最近的证据表明，干扰素基因刺激物（STING）途径可能代表多发性骨髓瘤中诱导抗肿瘤免疫反应的新靶点。在这里，我们研究了 STING 激动剂与硼替佐米联合或不联合检查点抑制剂治疗 MM 的抗肿瘤作用。
方法
通过免疫组织化学染色检查 58 例 MM 患者骨髓浆细胞中的 STING 表达。在免疫功能正常的 MM （Vκ*MYC）同种移植小鼠模型中体内评估拟议疗法的有效性。流式细胞术用于评估肿瘤负担并研究针对 MM 的免疫反应激活。ELISA 用于测量治疗后血清炎症细胞因子浓度。
结果
与单独使用任一化合物相比，STING 激动剂[2'3'-cGAM（PS）]与硼替佐米联合使用可显著降低肿瘤负担并改善治疗小鼠的生存率。联合治疗导致促炎细胞因子的分泌，并增加肿瘤微环境中中性粒细胞、活化树突状细胞和 T 细胞的百分比。然而，它还导致免疫细胞表面 PD-L1 的表达增加。添加抗 PD-1 抗体进一步增强了治疗效果。
结论
我们的研究结果表明，硼替佐米、STING 激动剂和检查点抑制剂组成的三药方案具有很高的抗骨髓瘤疗效。
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