背景:在最近的研究中,已经确定血管生成抑制剂可以提高免疫疗法的功效。然而,免疫治疗的延迟治疗效果对治疗计划提出了挑战.因此,本研究旨在探索非侵入性成像技术的潜力,特别是体素内不相干运动扩散加权成像(IVIM-DWI)和血氧水平依赖性磁共振成像(BOLD-MRI),在荷瘤动物模型中检测涉及免疫检查点阻断疗法和抗血管生成疗法的联合疗法的抗肿瘤反应。
方法:将小鼠MC-38细胞植入C57BL/6小鼠,建立结肠癌异种移植模型,并随机分为对照组,抗PD-1治疗组,联合治疗组(VEGFR-2抑制剂联合抗PD-1抗体治疗)。所有的小鼠都在之前成像,在3号,6th,9th,给药后第12天,同时进行病理检查。
结果:联合治疗组有效抑制肿瘤生长,与抗PD-1组(56.71%)相比,显示出显着更高的肿瘤抑制率,为69.96%。IVIM-DWI的f值和D*值在反映肿瘤血管生成方面表现出优势。D*值与CD31的相关性最高(r=0.702,P=0.001),f值与血管成熟度最密切相关(r=0.693,P=0.001)。而BOLD-MRI参数,R2*值,显示与Hif-1α的相关性最高(r=0.778,P<0.001),表明BOLD-MRI评估肿瘤缺氧的能力。此外,IVIM-DWI的D值与肿瘤细胞增殖密切相关,凋亡,淋巴细胞浸润.D值与Ki-67高度相关(r=-0.792,P<0.001),TUNEL(r=0.910,P<0.001)和CD8a(r=0.918,P<0.001)。
结论:VEGFR-2抑制剂联合PD-1免疫治疗对小鼠结肠癌模型具有协同抗肿瘤作用。IVIM-DWI和BOLD-MRI有望用作非侵入性方法,为肿瘤反应检测和疗效评估提供基于成像的证据。
Angiogenesis inhibitors have been identified to improve the efficacy of immunotherapy in recent studies. However, the delayed therapeutic effect of immunotherapy poses challenges in treatment planning. Therefore, this study aims to explore the potential of non-invasive imaging techniques, specifically intravoxel-incoherent-motion diffusion-weighted imaging (IVIM-DWI) and blood oxygenation level-dependent magnetic resonance imaging (BOLD-MRI), in detecting the anti-tumor response to the combination therapy involving immune checkpoint blockade therapy and anti-angiogenesis therapy in a tumor-bearing animal model.
The C57BL/6 mice were implanted with murine MC-38 cells to establish colon cancer xenograft model, and randomly divided into the control group, anti-PD-1 therapy group, and combination therapy group (VEGFR-2 inhibitor combined with anti-PD-1 antibody treatment). All mice were imaged before and, on the 3rd, 6th, 9th, and 12th day after administration, and pathological examinations were conducted at the same time points.
The combination therapy group effectively suppressed tumor growth, exhibiting a significantly higher tumor inhibition rate of 69.96% compared to the anti-PD-1 group (56.71%). The f value and D* value of IVIM-DWI exhibit advantages in reflecting tumor angiogenesis. The D* value showed the highest correlation with CD31 (r = 0.702, P = 0.001), and the f value demonstrated the closest correlation with vessel maturity (r = 0.693, P = 0.001). While the BOLD-MRI parameter, R2* value, shows the highest correlation with Hif-1α(r = 0.778, P < 0.001), indicating the capability of BOLD-MRI to evaluate tumor hypoxia. In addition, the D value of IVIM-DWI is closely related to tumor cell proliferation, apoptosis, and infiltration of lymphocytes. The D value was highly correlated with Ki-67 (r = - 0.792, P < 0.001), TUNEL (r = 0.910, P < 0.001) and CD8a (r = 0.918, P < 0.001).
The combination of VEGFR-2 inhibitors with PD-1 immunotherapy shows a synergistic anti-tumor effect on the mouse colon cancer model. IVIM-DWI and BOLD-MRI are expected to be used as non-invasive approaches to provide imaging-based evidence for tumor response detection and efficacy evaluation.