B Cells in Pancreatic Tumorigenesis
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer death in the United States. Despite a decline in overall cancer death rates, both incidence and death rates are steadily increasing for PDAC. Thus, new treatment strategies are urgently needed. Pancreatic cancer cells are surrounded by the dense stroma consisting of extracellular matrix and noncancerous cells, including fibroblasts and immune cells. Interactions between tumor cells and the associated stroma are critical for tumor growth and therapeutic response. PDAC in particular exhibits an extensive stromal response and low vessel density, resulting in tumor hypoxia, or oxygen deprivation. We recently demonstrated that disrupting hypoxia adaptation accelerates pancreatic cancer development and is accompanied by prominent accumulation of B cells in pancreatic tissues. Importantly, B cell depletion inhibits pancreatic tumorigenesis, implicating B cells as a tumor-promoting immune component in PDAC. The major goal of the studies outlined in this proposal is to further dissect B cell recruitment and function in pancreatic cancer. In Specific Aim 1, we will elucidate the mechanism by which hypoxia regulates the main B-cell chemo-attractant CXCL13 in PDAC. Using a three-dimensional organoid culture system of human PDAC tumor cells and fibroblasts, we will investigate the impact of hypoxia on tumor cells, fibroblasts, and their interactions to modulate CXCL13 expression. In Specific Aim 2, we will define the roles of B cell subpopulations in PDAC. To accomplish this, we will reconstitute B cell-deficient mice with different B cell subsets, implant pancreatic cancer cells into these animals, and compare tumor growth. The successful completion of these aims will improve our understanding of the regulation and function of B cells in pancreatic cancer. Significantly, since there are already US Food and Drug Administration (FDA)-approved drugs targeting B cells such as the Bruton tyrosine kinase (BTK) inhibitor Ibrutinib and anti-CD20 monoclonal antibody Rituximab, knowledge gained from studying B cell function in PDAC could be readily translated into meaningful PDAC patient benefit. Immunotherapy has shown great promise against multiple deadly cancers. However, single-agent immunotherapy has had little effect in PDAC. This is in part due to its immune suppressive microenvironment, driven by interactions between tumor cells, fibroblasts, and immune cells. My long-term goal is to understand the complex tumor-stroma interactions that shape the pancreatic tumor microenvironment, and to develop novel therapeutics aimed at manipulating these dynamics. My career goal is to become a valuable member of the pancreatic cancer research field and a future leader in the tumor microenvironment community. The Department of Defense Peer Reviewed Cancer Research Program Career Development Award will enable me to develop and expand my scientific knowledge and skill set and efficiently execute the proposed research.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010629
Entities
People
- Kyoung Lee
Organizations
- United States Army
- University of Michigan