Department of Anatomy, University of California, San Francisco, CA 94143-0452, USA.
Department of Radiology, Stanford University, Stanford, CA 94306, USA.
Drug Resist Updat. 2017 Nov;33-35:23-35. doi: 10.1016/j.drup.2017.10.001. Epub 2017 Oct 14.
The advent of cancer immunotherapy (CIT) and its success in treating primary and metastatic cancer may offer substantially improved outcomes for patients. Despite recent advancements, many malignancies remain resistant to CIT, among which are brain metastases, a particularly virulent disease with no apparent cure. The immunologically unique niche of the brain has prompted compelling new questions in immuno-oncology such as the effects of tissue-specific differences in immune response, heterogeneity between primary tumors and distant metastases, and the role of spatiotemporal dynamics in shaping an effective anti-tumor immune response. Current methods to examine the immunobiology of metastases in the brain are constrained by tissue processing methods that limit spatial data collection, omit dynamic information, and cannot recapitulate the heterogeneity of the tumor microenvironment. In the current review, we describe how high-resolution, live imaging tools, particularly intravital microscopy (IVM), are instrumental in answering these questions. IVM of pre-clinical cancer models enables short- and long-term observations of critical immunobiology and metastatic growth phenomena to potentially generate revolutionary insights into the spatiotemporal dynamics of brain metastasis, interactions of CIT with immune elements therein, and influence of chemo- and radiotherapy. We describe the utility of IVM to study brain metastasis in mice by tracking the migration and growth of fluorescently-labeled cells, including cancer cells and immune subsets, while monitoring the physical environment within optical windows using imaging dyes and other signal generation mechanisms to illuminate angiogenesis, hypoxia, and/or CIT drug expression within the metastatic niche. Our review summarizes the current knowledge regarding brain metastases and the immune milieu, presents the current status of CIT and its prospects in targeting brain metastases to circumvent therapeutic resistance, and proposes avenues to utilize IVM to study CIT drug delivery and therapeutic efficacy in preclinical models that will ultimately facilitate novel drug discovery and innovative combination therapies.
癌症免疫疗法 (CIT) 的出现及其在治疗原发性和转移性癌症方面的成功为患者带来了显著改善的治疗效果。尽管最近取得了进展，但许多恶性肿瘤仍然对 CIT 具有抗性，其中包括脑转移，这是一种特别致命的疾病，目前尚无明显的治愈方法。大脑具有独特的免疫学特征，这在肿瘤免疫学中引发了一些引人关注的新问题，例如组织特异性免疫反应差异、原发性肿瘤和远处转移之间的异质性，以及时空动态在塑造有效抗肿瘤免疫反应中的作用。目前用于研究脑转移的免疫生物学的方法受到组织处理方法的限制，这些方法限制了空间数据的收集，忽略了动态信息，并且无法再现肿瘤微环境的异质性。在当前的综述中，我们描述了高分辨率、活体成像工具，特别是活体显微镜 (IVM)，如何在回答这些问题方面发挥重要作用。临床前癌症模型的 IVM 能够进行短期和长期的关键免疫生物学和转移性生长现象的观察，有可能为脑转移的时空动态、CIT 与其免疫成分的相互作用以及化学疗法和放射疗法的影响带来革命性的见解。我们描述了通过跟踪荧光标记细胞（包括癌细胞和免疫亚群）的迁移和生长，同时使用成像染料和其他信号生成机制监测光学窗口内的物理环境，来研究小鼠脑转移的 IVM 的实用性，以阐明血管生成、缺氧和/或 CIT 药物在转移灶内的表达。我们的综述总结了有关脑转移和免疫微环境的现有知识，介绍了 CIT 的现状及其在靶向脑转移以规避治疗抵抗方面的前景，并提出了利用 IVM 研究 CIT 药物递送和临床前模型治疗效果的途径，最终将促进新药发现和创新联合疗法。
