CD47纳米药物联合αPD-L1的抗肿瘤免疫治疗研究

Combination of CD47-based nanoparticles andαPD-L1 for antitumor immunotherapy

目的研究CD47纳米药物联合抗程序性死亡-配体1单抗(αPD-L1)的抗肿瘤免疫治疗效果。方法采用BALB/c小鼠构建4T1乳腺癌荷瘤小鼠肿瘤模型,将CD47纳米药物与αPD-L1联用,考察联合治疗对4T1乳腺癌荷瘤小鼠局部肿瘤复发肿瘤的生长体积、生存时间以及肺转移的影响,并评价其诱导的体内免疫记忆效应,包括小鼠血清中细胞因子及小鼠脾脏中效应记忆T细胞表达。结果CD47纳米药物与αPD-L1联合治疗,可以有效抑制荷瘤小鼠局部肿瘤的复发,显著延长荷瘤小鼠生存时间(P<0.001)。同αPD-L1组相比,CD47纳米药物与αPD-L1联合治疗能明显提高小鼠血清中细胞因子肿瘤坏死因子-α(TNF-α)和干扰素-γ(IFN-γ)表达(均P<0.05),并明显增加小鼠脾脏中效应记忆T细胞的表达(P<0.001)。此外,4T1-Luc乳腺肿瘤荷瘤小鼠肺转移模型实验结果表明,CD47纳米药物与αPD-L1联合治疗可有效抑制肿瘤肺转移。结论CD47纳米药物与αPD-L1联用可通过肿瘤杀伤、CD47免疫检查点阻断和αPD-L1免疫检查点阻断的协同作用,进一步增强免疫检查点阻断的抗肿瘤免疫治疗效果。

Objective To investigate the therapeutic efficacy of the combination therapy with CD47-based nanoparticles and anti-PD-L1 monoclonal antibody(αPD-L1)for preventing tumor recurrence and metastasis in vivo.Methods BALB/c mice were used to construct 4T1 tumor-bearing mouse models.The mouse model was treated with the combination therapy to analyze the effects on local tumor recurrence,tumor growth volume,survival time and lung metastasis in the 4T1 mammary tumor-bearing mouse model.Results The combination therapy could effectively inhibit local tumor recurrence and prolong the survival time of tumor-bearing mice(P<0.001).Compared with theαPD-L1 group,the combination therapy can increase the expression of cytokines tumor necrosis factor-α(TNF-α)and interferon-γ(IFN-γ)in mouse serum(all P<0.05)and effector memory T cells in mouse spleen(P<0.001).In addition,the results on the 4T1-Luc mammary tumor-bearing mouse lung metastasis model showed that the combination therapy could effectively inhibit tumor lung metastasis.Conclusions The results strongly suggested that combination therapy with CD47-based nanoparticles andαPD-L1 can effectively elicit the memory immune response,and prevent tumor recurrence and lung metastasis.