整合素αn vβn 3放射性核素靶向治疗联合PD-L1免疫治疗的实验研究n

来源 :中华核医学与分子影像杂志 | 被引量 : 0次 | 上传用户:yutianweixiuwang
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目的:探讨基于靶向整合素αn vβn 3的放射性核素靶向治疗(TRT)联合基于程序性死亡受体蛋白配体1(PD-L1)的免疫治疗的抗肿瘤疗效及其潜在机制。n 方法:制备可特异性靶向整合素αn vβn 3的分子探针n 177Lu-伊文思蓝(EB)-精氨酸-甘氨酸-天冬氨酸(RGD),并测定其放射性比活度与放化纯。建立结肠癌MC38荷瘤鼠模型,进行生物分布及microSPECT显像研究。通过监测小鼠肿瘤体积和体质量变化来评估疗效与安全性(各组n n=9);采用流式细胞术分析A组(对照组;生理盐水治疗)、B组(n 177Lu-EB-RGD单药治疗,18.5 MBq)、C组(PD-L1抗体单药治疗,10 mg/kg)和D组(联合治疗,18.5 MBq n 177Lu-EB-RGD与10 mg/kg PD-L1)荷瘤鼠经治疗后肿瘤微环境(PD-L1n +免疫细胞、CD8n +T细胞和调节性T细胞)的改变(各组n n=3)。采用重复测量方差分析、两独立样本n t检验分析数据。n 结果:177Lu-EB-RGD放射性比活度为(55.85±14.00) GBq/μmol,放化纯大于95%。MicroSPECT显像中,n 177Lu-EB-RGD在荷瘤鼠肿瘤中清晰可见,且摄取率高、滞留时间长,注射后24 h肿瘤/肌肉比值达14.87±0.88,而在正常组织摄取及滞留较少;生物分布结果显示,注射后4 h n 177Lu-EB-RGD较n 177Lu-RGD表现出明显增高的肿瘤摄取[(12.00±1.60)和(3.69±0.37)每克组织百分注射剂量率(%ID/g);n t=8.63,n P<0.01]。在治疗开始后第6天,A~D各组小鼠肿瘤体积差异有统计学意义(n F=7.32,n P=0.03),在监测时间内,D组平均肿瘤体积最小,治疗效果最好,7/9的荷瘤鼠表现为完全缓解,且未出现肿瘤复发。流式细胞术结果显示,TRT可导致肿瘤微环境中PD-L1表达上调,B组与A组PD-L1n +免疫细胞数差异有统计学意义(CD45n +/PD-L1: 2.34%与0.95%,CD11bn +/PD-L1:2.41%与0.66%;n t值:11.17和8.70,均n P<0.01),而免疫治疗及联合治疗使C、D组微环境中的CD8n +T细胞浸润较A组急剧增加(2.07%与0.26%,2.71%与0.26%;n t值:4.10和6.03,均n P<0.05)。n 结论:TRT联合免疫治疗可协同增强抗肿瘤疗效,有望应用于可接受TRT的转移性肿瘤患者的治疗。“,”Objective:To investigate the therapeutic efficacy and potential mechanisms of integrin α n vβn 3-targeted radionuclide therapy (TRT) in combination with anti-programmed cell death protein ligand 1 (PD-L1) immunotherapy.n Methods:Integrin α n vβn 3-targeted molecule Arg-Gly-Asp (RGD) was conjugated with Evans blue (EB) and then labeled with n 177Lu to obtain n 177Lu-EB-RGD. The radioactivity and radiochemical purity were determined. MicroSPECT imaging, biodistribution, and n in vivo therapeutic efficacy were subsequently performed in MC38 murine colon cancer models. Volume of tumor and body mass of mice were observed to assess the therapeutic efficacy and safety (n n=9 in each group). Flow cytometry was used to evaluate therapy response of saline-treated (control, group A), 18.5 MBq n 177Lu-EB-RGD-treated (group B), 10 mg/kg PD-L1 antibody-treated (group C), TRT combined with immunotherapy-treated (group D, 18.5 MBq n 177Lu-EB-RGD and 10 mg/kg PD-L1 antibody) mice and alterations in tumor microenvironment (PD-L1n + immune cells, CD8n + T cells and regulatory T cells). Independent-sample n t test and repeated measures analysis of variance were used for data analysis.n Results:The radioactivity of n 177Lu-EB-RGD was (55.85±14.00) GBq/μmol. SPECT imaging clearly visualized the MC38 tumors in mice models with high uptake and long retention time, the tumor/muscle ratio reached 14.87±0.88 at 24 h postinjection, while less uptake and retention in normal tissues. Tumor uptake ofn 177Lu-EB-RGD was significantly higher than that of n 177Lu-RGD 4 h post-injection ((12.00±1.60) n vs (3.69±0.37) %ID/g; n t=8.63, n P<0.01). The efficacy results between each treatment group was significantly different (n F=7.32, n P=0.03) at day 6 post-treatment. The combination therapy showed the most outstanding anti-tumor efficacy with 7/9 mice showed complete response. Flow cytometry results showed that TRT up-regulated the PD-L1 expression significantly, namely, PD-L1n + immune cells in group B and group A were significantly different (CD45n + /PD-L1: 2.34% n vs 0.95%, CD11bn + /PD-L1: 2.41% n vs 0.66%; n t values: 11.17 and 8.70, both n P<0.01); immunotherapy and combination therapy dramatically stimulated the infiltration of CD8n + T cells (2.07% n vs 0.26%, 2.71% n vs 0.26%; n t values: 4.10 and 6.03, both n P<0.05).n Conclusion:TRT in combination with immunotherapy synergistically enhance anti-tumor efficacy, which is expected to play a role in the treatment of patients with advanced tumor where TRT can be applied.
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