Imaging Immune Cell Modulation in Cancer Therapy

免疫细胞在癌症的发展、维持、侵袭和转移中起关键作用。然而，在这方面， 虽然一些特定的细胞相互作用和功能已被较好地理解， 癌症中的免疫反应仍然完全未知。几个突出的问题包括：（a）如何 在不同的癌症之间实时发生相互作用？B）细胞毒性和其他抗癌药物如何 药物影响肿瘤中复杂的免疫网络？以及c）利用免疫功能的药物可以 以协同方式使用以增强抗癌功效？直到最近， 这是一个问题的答案，因为不可能将免疫细胞在它们的自然状态下可视化。 微环境在这个项目中，我们将使用实时成像系统地对关键免疫细胞进行成像 技术，并研究不同的抗癌疗法如何影响他们的行为。我们假设 通常使用的药物确实会影响免疫细胞的行为，并且可以选择和/或 组合以提供加性协同抗肿瘤作用。我们的具体目标如下：1） 确定肿瘤浸润的免疫细胞网络在小鼠模型中的组成和功能， 结肠腺癌我们通过首先建立所有必要的活体成像工具来实现这一点。 2)确定抗癌药物如何调节结肠癌小鼠模型中的免疫网络 腺癌为了实现这一目标，我们将研究常用的细胞毒性药物，新的和有前途的 分子靶向药物以及NCI顶级免疫药物。个体药物效应将是 首先研究，然后再研究合理选择的药物组合的效果。3)到 将我们最有前途的治疗方案扩展到原位和转基因小鼠癌症模型， 更好地复制人类疾病。通过测量治疗，将进一步促进临床翻译 使用临床相关读数的反应。最终，我们的目标是修改目前的治疗方案， 治疗癌症为此，由于拟议的工作重点是评估临床批准的药物， 我们的发现不仅具有很高的临床意义，而且可以迅速翻译。这个项目 将采用创新方法实时研究免疫相互作用和功能。将合并的 使用人类疾病的基因工程小鼠模型以及最先进的显微镜 将通过富有成效的合作促进成像方法。

Immune cells play a key role in cancer development, maintenance, invasion and metastases. However, while some specific cellular interactions and functions are relatively well understood, other aspects of immune responses in cancer remain entirely unknown. Several outstanding questions include: a) how do interactions occur in real-time in vivo across different cancers? b) how do cytotoxic and other anti-cancer drugs affect the complex immune network in tumors? and c) can drugs that harness immune function be used in a synergistic fashion to enhance anti-cancer efficacy? Until recently it has been difficult to answer such questions since it has not been possible to visualize immune cells within their natural microenvironment. In this project, we will systematically image key immune cells using real-time imaging technologies, and investigate how different anticancer therapies affect their behavior. We hypothesize that commonly used drugs do indeed affect immune cell behavior, and that they can be chosen and/or combined so as to offer additive synergistic anti-tumor effects. Our specific aims are as follows: 1) To determine the composition and function of tumor-infiltrated immune cell networks in a mouse model of colon adenocarcinoma. We achieve this by first establishing all the necessary tools for intravital imaging. 2) To determine how anti-cancer drugs modulate immune networks in the mouse model of colon adenocarcinoma. To achieve this, we will investigate commonly used cytotoxic drugs, new and promising molecularly targeted agents, as well as NCI top-listed immune agents. Individual drug effects will be studied first, before subsequently investigating the effects of rationally selected drug combinations. 3) To extend our most promising treatment regimen to orthotopic and transgenic mouse cancer models, which better replicate human disease. Clinical translation will be further facilitated by measuring treatment responses using clinically relevant readouts. Ultimately, our goal is to revise current therapeutic options for cancer. To this end, because the proposed work is focused on evaluating clinically approved agents, our findings will not only have high clinical significance but will also be rapidly translatable. This project will employ innovative approaches to study immune interactions and function in real-time. The combined use of genetically engineered mouse models of human disease together with state-of-the-art microscopic imaging approaches will be facilitated through productive collaborations.