Collaborative Innate-Adaptive Immune Regulation of Tumor Progression

描述（由申请人提供）：免疫系统对不断发展的肿瘤有反应，那么为什么它不能根除肿瘤？识别肿瘤特异性抗原的T细胞克隆在癌症患者体内扩增，但肿瘤很少会被免疫系统自发根除。同样，增强T细胞的免疫疗法虽然显示出一些功效，但效率低下。免疫反应似乎经常在肿瘤微环境中受阻。在那里，T细胞暴露于抑制和刺激信号，以可溶性或细胞表面来源的刺激的形式。关于肿瘤反应性免疫细胞如何在自然进化的肿瘤微环境中发挥功能和行为，还有很多尚不清楚。我们对T细胞和抗原呈递，肿瘤中的先天免疫细胞之间发生的动态相互作用的类型视而不见。然而，利用可成像的小鼠模型，现在可以在肿瘤微环境中原位完全解决免疫系统先天臂和适应性臂协作的性质。基于初步数据，我们假设先天免疫细胞群体在微环境中调节适应性免疫系统的细胞，保护肿瘤免受免疫攻击。利用我们在小鼠癌症模型中同时成像先天和适应性免疫细胞的能力，我们将对肿瘤中发生的免疫细胞相互作用的类型进行评估。我们将讨论适应性T细胞和先天抗原提呈细胞之间的相互作用如何受到微环境和肿瘤类型的影响，以及它如何随着肿瘤进展而演变。我们将进一步寻求确定参与先天和适应性免疫反应之间协作的途径。最后，我们将使用我们的模型来可视化和定义免疫和细胞毒性治疗对免疫反应的实时影响。在这一点上，直接成像将指导治疗的发展和优化。在整个过程中，我们还将与临床研究人员协调进行人体活检样本的同步分析，以将我们的发现转化为诊断和治疗。

DESCRIPTION (provided by applicant): The immune system reacts to the evolving tumor, so why does it not eradicate tumors? T cell clones that recognize tumor-specific antigens are expanded in cancer patients, yet tumors are rarely spontaneously eradicated by the immune system. Similarly, immune therapies that boost T cells, though showing some efficacy, are inefficient. It appears that the immune response frequently is stymied in the tumor microenvironment. There, T cells are exposed to inhibitory and stimulatory signals, either in the form of soluble or cell-surface derived stimuli. Much is still unclear about how tumor-reactive immune cells function and behave in the microenvironment of naturally evolving tumors. We have literally been blind to the types of dynamic interactions that occur between T cells and antigen presenting, innate immune cells in tumors. However, the nature of the collaboration of the innate and adaptive arms of the immune system can now be fully addressed in situ, within the tumor microenvironment, using mouse models accessible to imaging. Based on preliminary data, we hypothesize that a population of innate immune cells regulate the cells of the adaptive immune system in the microenvironment, protecting the tumor from immune attack. Capitalizing on our ability to concomitantly image innate and adaptive immune cells in situ in mouse models of cancer, we will undertake an assessment of the types of immune cell interactions that occur in the tumor. We will address how interactions between adaptive T cells and innate antigen presenting cells are influenced by microenvironments and by tumor types and how it evolves with tumor progression. We will further seek to identify pathways involved in the collaboration between the innate and adaptive immune responses. Finally, we will use our models to visualize and define what immune and cytotoxic therapy does to the immune response in real-time. In this latter point, direct imaging will guide the development and optimization of therapies. Throughout, we will also coordinate with clinical researchers to undertake concurrent analyses of human biopsy samples to translate our findings into diagnosis and therapy.