Stacy K. Thomas (Mentor: Gregory Beatty, MD, PhD)

“Beta-glucan treatment restricts liver metastasis of pancreatic cancer”

Stacy K. Thomas, Jae W. Lee, Meredith L. Stone, Max M. Wattenberg, Gregory L. Beatty

Pancreatic ductal adenocarcinoma (PDAC) has one of the worst 5-year survival rates of all human cancers: a mere 10%. For most patients, metastatic disease is the main cause of mortality with the liver being the most common site of metastasis. Our previous work demonstrated that a primary pancreatic tumor triggers production of soluble factors, which instruct the formation of a pro-metastatic niche in the liver. Macrophages are a predominant component of this liver niche, yet their role in regulating metastasis remains ill-defined. My data suggest that, in the absence of a pro-metastatic niche, liver macrophages do not restrict or promote tumor cell seeding in the liver. In contrast, published data show that liver macrophages can promote tumor outgrowth once seeding has already occurred. Together, these findings imply that macrophage are coopted to support tumor growth and thus might be retrained to fight cancer. Treatment with myeloid agonists like beta-glucans can alter macrophage biology. In vitro studies suggest that macrophages treated with beta-glucan have a M1-like phenotype and have increased phagocytic capacity.  My data show that in vivo beta-glucans bind liver macrophages and inhibit liver metastasis. Histological analysis of metastatic lesions in beta-glucan treated mice demonstrate smaller lesions, decreased proliferating tumor cells and increased numbers of T cells at the periphery of the lesions. This restriction of metastasis is dependent on phagocytic cells, which include macrophages, as well as T cells.  Together, these findings suggest that myeloid agonists, such as beta-glucans, may be able to engender macrophages with the ability to restrict liver metastasis. Future work aims to elucidate the roles of distinct liver macrophage subsets, including Kupffer cells and bone marrow derived macrophages, in the anti-metastatic activity of beta-glucans and the relationship between macrophages and other cell types in the metastatic microenvironment, including tumor cells and T cells.