Collaborative Innate-Adaptive Immune Regulation of Tumor Progression

描述(申请人提供)：免疫系统对不断演变的肿瘤做出反应，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中会扩大，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定的疗效，但效果不佳。似乎免疫反应在肿瘤微环境中经常受到阻碍。在那里，T细胞暴露在抑制性和刺激性信号中，无论是以可溶性的形式还是以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作用和表现，仍有许多不清楚的地方。我们实际上忽视了T细胞和肿瘤中的抗原提呈、先天免疫细胞之间发生的动态相互作用的类型。然而，免疫系统先天和适应性手臂的协作性质现在可以在原位、在肿瘤微环境中完全解决，使用可以进行成像的小鼠模型。根据初步数据，我们假设一群天然免疫细胞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免疫细胞和获得性免疫细胞的能力，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，以及它是如何随着肿瘤进展而演变的。我们将进一步寻求确定参与先天免疫反应和获得性免疫反应之间合作的途径。最后，我们将使用我们的模型来实时可视化和定义免疫和细胞毒治疗对免疫反应的影响。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，对人体活检样本进行同步分析，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.