The most prevalent type of pancreatic cancer, pancreatic ductal adenocarcinoma (PDA) is a lethal cancer which has not seen substantial progress in survival rate in over four decades. Patients present most often with metastatic disease, for which there are no effective therapies. The disease is characterized by a complex tumor microenvironment that consists of fibroblasts and infiltrating immune cells, of a suppressive nature. This suppressive, cellular cross-talk exists both in the primary tumor and at sites of metastases. It is known that other cell types, such as immune cells, arrive to these distal sites preceding tumor cell dissemination. These sites are referred to as the pre-metastatic niche and remodel the distal organs to be favorable for tumor cell colonization and growth. Recently, immune checkpoint inhibitors have shown success in other cancers, specifically melanoma, but have shown little success in pancreatic cancer. Our lab, and others, has shown the importance of myeloid cells in establishing immune suppression at the primary tumor. What remains unknown is how the pre-metastatic niche is established. My data show that Apolipoprotein E (ApoE) is differentially expressed in the pre-metastatic niche of tumor-bearing animals. This niche has a robust myeloid population that expresses ApoE, and is sparsely populated by cytotoxic T cells, indicative of immune suppression at these distal sites. The overall objective is to understand the cellular interactions that lead to the establishment of the immunosuppressive pre- metastatic niche in pancreatic cancer. The central hypothesis is that ApoE contribute to the immunosuppressive nature of the pancreatic cancer microenvironment at the primary and metastatic sites (Aim 1) and modulates macrophage polarization and function of TAMs, regulating T cell activity (Aim 2). To test my hypothesis, I will use biomaterial scaffolds to study the pre-metastatic niche in vivo. Scaffolds are able to recapitulate the pre-metastatic niche and will allow me to characterize the cellular infiltrate and discover novel targets to block pre-metastatic niche establishment. These experiments will give mechanistic data on the role of myeloid cells in establishing the pre-metastatic niche in pancreatic cancer.
Pancreatic ductal adenocarcinoma is an almost universally fatal disease, in part due to its immunosuppressed tumor microenvironment. The myeloid cells that are present are of a suppressive nature and prevent cytotoxic, CD8+ T cell activity from killing the tumor cells, through various mechanisms. The mechanism for how myeloid cells establish this microenvironment at metastatic sites remains unknown, and will be the question this proposal addresses.
