Date of Award

August 2013

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Biological Sciences

First Advisor

Douglas A. Steeber

Committee Members

Ava Udvadia, Jeri-Anne Lyons, Reinhold Hutz, Julie Oliver, Douglas Steeber

Keywords

Breast Cancer, L-Selectin, Lymphocyte, Migration, Regulatory T Cell

Abstract

Regulatory T (Treg) cells mediate tumor immune evasion by suppressing anti-tumor effector T cell responses in peripheral lymphoid tissues and within the tumor. While elevated Treg cell numbers have been shown to correlate with increased tumor growth, mechanisms that regulate their distribution within secondary lymphoid tissue and tumor tissue are not well understood. L-selectin, an adhesion molecule constitutively expressed on all classes of leukocytes, functions early in the adhesion cascade and regulates the migration of lymphocytes to lymph nodes through high endothelial venules. In addition, L-selectin can mediate migration of lymphocytes to sites of inflammation by binding to ligands present on inflamed endothelium. Treg cells express high levels of L-selectin and require L-selectin for entry into resting lymph nodes. However, the role of L-selectin in regulating Treg cell distribution and migration into tumors and lymph nodes during chronic inflammation, such as cancer, has not been examined. Therefore, we investigated the role of L-selectin in regulating Treg cell rolling and adhesion to an endothelial cell monolayer in vitro as well as the distribution and migratory patterns of Treg cells using the murine 4T1 breast cancer model. Importantly, ɑ4ɑ7 integrin/VCAM-1 interactions were found to significantly contribute to Treg cell adhesion to endothelial cell monolayers under shear stress only in the presence of L-selectin function. In vivo, Treg cell populations preferentially accumulated in tumors and tumor-draining lymph nodes during progression of disease, and increased at higher rates than conventional CD4+ T cell populations as tumors progressed. Furthermore, Treg cells preferentially migrated to tumors and tumor-draining lymph nodes in a L-selectin-dependent manner, thereby promoting immune suppressive environments. These studies provide further insight into the mechanisms of L-selectin function in regulating Treg cell distribution during chronic inflammation such as cancer, and may lead to a better understanding of tumor immune evasion and provide new targets for immunotherapeutic strategies.

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