The Role of Immune Cells on Irradiated Tumor Microenvironment

There were extensive studies on the mechanisms of radiation-induced normal organ damage, however, the works on the responses of tumor microenvironment following in vivo RT are much less in the literature, and the response and interaction for each cellular component is still unclear. In recent 3 years we have worked in this field, with an initial intent to characterize the changes of tumor-associated macrophages (TAMs) and vascular responses during the single-dose and fractionated-dose RT. This project is a continuous work of our present NSC grant and its overall aim is to study the role of immune cells on tumor microenvironment and tumor responses after in vivo radiotherapy (RT), and on tumor bed effects (TBE). In the present NSC grant, we have identified that TAMs in the irradiated tumors expressed high levels of Arginase-1 and COX-2, and promote tumor growth (Int. J. Radiat. Oncol. Biol. Phys., 2007). Most recently we found the decrease of microvascular density (MCD) in the irradiated tumors transformed tumor from transient (vascular dysfunction) to chronic hypoxia (vascular insufficiency), and aggregation of CD-68+ TAMs in the hypoxia region (in press, Clin. Cancer Res.). These two papers showed immune cells and vascular responses have essential roles on post-irradiation tumor microenvironment in supporting tumor regrowth. Our preliminary data showed that un-irradiated tumor cells growing in pre-irradiated tissues had similar vascular and immune cell responses as those in the regrowing tumors after RT, so-called “tumor bed effects”. Based on these previous works, we plan to dissect the role of TAMs in the irradiated tumors, study the HIF-1alpha expression in the irradiated tumors, and characterize the expression pattern of immune cells and study the role of TAMs in the tumor bed effects. This project will clarify the role of immune cells in these two types of tumor microenvironments and their relation with angiogenic response. . Our specific aims are: 1. To study the role of TAMs on tumor microenvironment and regrowth after RT by depleting CD11b+ TAMs. 2. To make a comprehensive study in knowing the changes of HIF-1 in irradiated tumors and identify cells responsible for its expression. 3. To explore the role of TAMs in un-irradiated tumors growing from pre-irradiated tissue (tumor bed effects). A. To study the vascular and TAMs responses and find out their association. B. To study the spatial and chronological changes of different immune cells in the tumors growing from irradiated tissues, their association with sub-components and their phenotype and gene expression. C. To study the role TAMs on tumor bed effects by depleting CD11b+ TAMs

Project ID:PC9902-1655 
External Project ID:NSC98-2628-B182-002-MY3