Imaging Immune Cell Modulation in Cancer Therapy

免疫细胞在癌症的发生、维持、侵袭和转移中起着关键作用。然而， 虽然一些特定的细胞相互作用和功能相对较好地理解，但 癌症中的免疫反应仍然完全未知。一些悬而未决的问题包括：a)如何 不同癌症之间的相互作用在体内是实时发生的？B)细胞毒性和其他抗癌药物是如何 药物会影响肿瘤的复杂免疫网络吗？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疗效？直到最近，一直很难做到 回答这样的问题，因为还不可能看到免疫细胞在其自然状态下 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，并调查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影响免疫细胞的行为，并且可以选择和/或 组合以提供相加的协同抗肿瘤作用。我们的具体目标如下：1) 确定肿瘤浸润性免疫细胞网络的组成和功能 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小鼠模型的免疫网络 腺癌。为了实现这一点，我们将研究常用的细胞毒药物，新的和有希望的 分子靶向制剂，以及NCI排名靠前的免疫制剂。个别药物的影响将是 首先研究，然后再调查合理选择药物组合的效果。3)至 将我们最有希望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，我们的目标是修改当前的治疗方案 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，而且还可以快速翻译。这个项目 将使用创新的方法来实时研究免疫相互作用和功能。合并后的 利用人类疾病的基因工程小鼠模型和最先进的显微技术 成像方法将通过富有成效的合作得到促进。

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.