THE EPHA2/EPHRIN-A1 AXIS REGULATES HOST-TUMOR INTERACTIONS
Shiuan, Eileen Fong
Despite significant advancements in cancer research, prevention, and therapeutics, cancer remains a major public health problem. The EphA2 receptor tyrosine kinase and ephrin-A1 ligand signaling axis has long been implicated in solid cancers, including lung and breast cancer, as well as other pathological processes, such as inflammation. The majority of research on this axis has focused on EphA2’s tumor-promoting and ephrin-A1’s tumor-suppressing effects in the cancer cells. However, the EphA2/ephrin-A1 signaling axis not only exists within tumor cells, but also in many other cell types, such as endothelial and immune cells, and facilitates communication between different cell types. This dissertation examines the role of EphA2/ephrin-A1 axis among host-tumor interactions. In the first half of this dissertation, we investigate the impact of tumor-specific EphA2 on the host anti-tumor immune response T cell immune response. We discover that EphA2-overexpression in the tumor cell decreases T cell infiltration and particularly CD8 T cell activity via upregulation of monocyte-attracting chemokines that likely contribute to increased recruitment of macrophages and potential myeloid-derived suppressor cells observed in the EphA2-overexpressing tumors. In the second half of this dissertation, we evaluate the impact of host deficiency of ephrin-A1 on cancer growth and metastasis. Using ephrin-A1 knockout mice, we discover that ephrin-A1 deficiency in host tissues decreases lung metastasis of breast cancer cells by providing a less favorable metastatic niche. Together, these two parallel works consistently demonstrate that EphA2 and ephrin-A1 play important roles in modulating host-tumor interactions. These studies provide additional insight into the many complex interactions that the EphA2/ephrin-A1 axis regulates in the tumor microenvironment.
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