Date of Award

August 2015

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Biological Sciences

First Advisor

Douglas Steeber

Committee Members

Julie Oliver, Heather Owen, Reinhold Hutz, Jeri-Annette Lyons

Abstract

Myeloid-derived suppressor cells (MDSC) consist of two major subsets, monocytic MDSC (M-MDSC) and polymorphonuclear MDSC (PMN-MDSC), both of which expand in cancer and suppress the activation of naïve T cells in the tumor-draining lymph node (TDLN) and the function of effector T cells in the tumor microenvironment. Thus, the ability of MDSC to enter the TDLN and the tumor is likely to be critical for suppression of the anti-tumor immune response. L-selectin mediates the homing of circulating naïve lymphocytes to lymph nodes and the migration of conventional myeloid cells, such as neutrophils and monocytes, to sites of inflammation, but its contribution to MDSC migration is unknown. Using the 4T1 murine breast cancer model, we demonstrated that MDSC express L-selectin and integrins necessary for migration to TDLN and inflammatory sites, such as the tumor. We then demonstrated involvement of L-selectin in the migration of PMN-MDSC, but not M-MDSC, to tumors and TDLN. This suggests that M-MDSC may utilize L-selectin-independent mechanisms for migration. After entry into the tumor, MDSC migrated through the tumor parenchyma and associated with MDSC aggregates localized in the immediate vicinity of hypoxic areas. BrdU incorporation experiments showed that approximately 20% of tumor-infiltrating MDSC were undergoing in situ proliferation in the tumor microenvironment. Thus, in addition to MDSC recruitment to tumors, intratumoral proliferation of MDSC may also contribute to MDSC accumulation. Hypoxia-inducible factor (HIF) is an intracellular sensor of hypoxia, which functions to activate the expression of genes necessary for adaptation to hypoxic conditions. There are several HIF isoforms with both overlapping and opposing roles in various processes, including proliferation. Although our preliminary experiments did not confirm a role for HIF in inducing proliferation of tumor-infiltrating MDSC, the specific roles of the different HIF isoforms in MDSC recruitment, proliferation, and function in the tumor microenvironment requires further study. These studies provide insights into the mechanisms of MDSC migration and accumulation in the tumor and TDLN. Further studies may create a basis for novel immunotherapeutic approaches for the treatment of cancer.

Available for download on Monday, October 23, 2017

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