My current research has focused on the CD8+ T cell response to infection within the tissue and how this is influenced by local inflammation. This application builds on my prior work, and seeks to examine the role of inflammation in directing productive tissue resident T cell responses to colorectal cancer. My immediate career goal is to acquire an independent faculty position, and subsequently, to lead a research program that focuses on T cell responses that develop in response to both pathogenic microorganisms and solid tumors in the intestinal tissue. The University of Washington is an excellent environment for training postdoctoral fellows to become independent research scientists. I have been supported by Dr. Bevan and the Department of Immunology in my research and professional development. The department has provided me with the opportunity to present my research and receive feedback, attend research seminars in a variety areas including cancer immunology, and encourages collaboration with affiliated institutions including Fred Hutchinson Cancer Research Center. Many of Dr. Bevan's trainees have gone on to establish successful research laboratories, and I believe I have also received the support and guidance necessary to secure a tenure-track faculty position. It is well established that CD8+ T cell infiltration into solid malignancies, including colorectal tumors, positively correlates with tumor control. The majority of intestinal CD8+ T cells are CD103+; however, after infection, a sizable population of CD103? cells develops in the lamina propria in response to inflammatory cues. We hypothesize that a CD103? CD8+ T cell population develops in the intestine during colorectal tumorigenesis and provides superior control of tumor growth, and that inflammation within the tumor microenvironment promotes the development and function of this T cell population. This proposal aims to establish a mouse model of colorectal tumor formation with a defined tumor-associated antigen that will allow us to address questions about the phenotype and function of tumor-specific CD8+ T cells, the role of CXCR3 in their recruitment into the tumor, and the role of IL-33 produced by tumor tissue in promoting effector function. I believe my earlier research addressing innate immunity and its influence on adaptive immune responses in the tissue provides me with the technical expertise and scientific knowledge to examine the role of inflammation in driving adaptive immune responses in colorectal tumor tissue. The funding provided by this award would provide me with the opportunity to generate reagents and perform the necessary experiments to address these questions and develop this new area of research in my laboratory.
Colorectal cancer is one of the most common malignancies among populations in the developing world, and the lifetime colorectal cancer risk among the general population is 5%. Cytotoxic CD8+ T cells are able to enter colorectal tumor tissue and control disease, and this study will identify host factors that enhance the function of this important T cell population in colorectal cancer.
