Martello Shannon E, Xia Jixin, Kusunose Jiro, Hacker Benjamin C, Mayeaux McKenzie A, Lin Erica J, Hawkes Adrienne, Singh Aparna, Caskey Charles F, Rafat Marjan
Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN, USA.
Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA.
Theranostics. 2024 Oct 21;14(18):6883-6896. doi: 10.7150/thno.97759. eCollection 2024.
While immunotherapy shows great promise in patients with triple negative breast cancer, many will not respond to treatment. Radiotherapy has the potential to prime the tumor-immune microenvironment for immunotherapy. However, predicting response is difficult due to tumor heterogeneity across patients, which necessitates personalized medicine strategies that incorporate tumor tracking into the therapeutic approach. Here, we investigated the use of ultrasound (US) imaging of the tumor vasculature to monitor the tumor response to treatment. We utilized ultrafast power doppler US to track the vascular response to radiotherapy over time. We used 4T1 (metastatic) and 67NR (non-metastatic) breast cancer models to determine if US measurements corroborate conventional immunostaining analysis of the tumor vasculature. To evaluate the effects of radiation, tumor volume and vascular index were calculated using US, and the correlation between vascular changes and immune cell infiltration was determined. US tumor measurements and the quantified vascular response to radiation were confirmed with caliper measurements and immunostaining, respectively, demonstrating a proof-of-principle method for non-invasive vascular monitoring. Additionally, we found significant infiltration of CD8 T cells into irradiated tumors 10 days after radiation, which followed a sustained decline in vascular index and an increase in splenic CD8 T cells that was first observed 1 day post-radiation. Our findings reveal that ultrafast power doppler US can evaluate changes in tumor vasculature that are indicative of shifts in the tumor-immune microenvironment. This work may lead to improved patient outcomes through observing and predicting response to therapy.
虽然免疫疗法在三阴性乳腺癌患者中显示出巨大的前景，但许多患者对治疗无反应。放射疗法有可能为免疫疗法优化肿瘤免疫微环境。然而，由于患者肿瘤的异质性，预测反应很困难，这就需要将肿瘤跟踪纳入治疗方法的个性化医疗策略。在此，我们研究了利用肿瘤血管的超声（US）成像来监测肿瘤对治疗的反应。我们利用超快功率多普勒超声来跟踪放疗后血管随时间的反应。我们使用4T1（转移性）和67NR（非转移性）乳腺癌模型来确定超声测量结果是否与肿瘤血管的传统免疫染色分析结果相符。为了评估放疗的效果，使用超声计算肿瘤体积和血管指数，并确定血管变化与免疫细胞浸润之间的相关性。超声肿瘤测量结果和对放疗的定量血管反应分别通过卡尺测量和免疫染色得到证实，证明了一种用于无创血管监测的原理验证方法。此外，我们发现放疗后10天，CD8 T细胞大量浸润到受照射的肿瘤中，这伴随着血管指数的持续下降以及放疗后1天首次观察到的脾脏CD8 T细胞数量的增加。我们的研究结果表明，超快功率多普勒超声可以评估肿瘤血管的变化，这些变化表明肿瘤免疫微环境发生了改变。这项工作可能通过观察和预测治疗反应来改善患者的治疗效果。
