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"Phosphatidylserine sensing by Tyro3, Axl, and Mertk (TAM) receptors regulate Programmed Death-Ligand 1 (PD-L1) and immune responses in breast cancer"

by
Canan Kasikara
Molecular Biology, Genetics & Cancer Track
B.S. 2011, Bilkent University, Turkey


Thesis Advisors: Raymond B. Birge, Ph.D.
Professor
Department of Microbiology, Biochemistry and Molecular Genetics

Monday, October 23, 2017
Cancer Center, G-1196


Abstract

Tyro3, Axl and Mertk (collectively TAM receptors) are three homologous receptor tyrosine kinases (RTKs) that bind vitamin K-dependent endogenous ligands, Protein S (ProS) and Growth arrest specific factor 6 (Gas6), and act as bridging molecules to promote phosphatidylserine (PS)-mediated clearance of apoptotic cells (efferocytosis). TAM receptors are overexpressed in a vast array of tumor types, whereby the level of expression not only correlates with the tumor grade and the emergence of chemo- and radio-resistance to targeted therapeutics, but also are implicated as inhibitory receptors on infiltrating myeloid-derived cells in the tumor microenvironment (TME) that can suppress host anti-tumor immunity. In the present study, we utilized TAM-IFNƒ×R1 reporter lines and expressed TAM receptors in a variety of epithelial cell model systems to show that each TAM receptor had a unique pattern of activation by Gas6 or ProS, as well as unique dependency for PS on apoptotic cells and PS liposomes for activity. In addition, we leveraged this system to engineer epithelial cells that express WT TAM receptors, and show that while each receptor can promote PS-mediated efferocytosis, AKT-mediated chemo-resistance, as well as up-regulate the immune checkpoint molecule PD-L1 on tumor cells, Mertk is most dominant in the aforementioned pathways. Functionally, TAM receptor-mediated efferocytosis could be partially blocked by PS-targeting antibody 11.31 and Annexin V, demonstrating the existence of a PS/PS-R (TAM-receptor)/PD-L1 axis that operates in epithelial cells to foster immune escape. Finally, we investigated the effect of combinational treatment targeting TAMs and PD-1 on tumor growth and host anti-tumor response. Our ¡§in vivo¡¨ results showed inhibition of TAM receptors with pan-TAM kinase inhibitors enhanced anti-tumor immunity over single agent treatments by decreasing tumor suppressive immune cell populations and increasing immunogenic cytokines in tumor microenvironment leading to decreased tumor growth and lung metastases. Taken together, studies in this dissertation provides mechanistic insight into the role of TAMs as negative regulators of the tumor immune microenvironment, and rationale for the development of TAM receptor antagonists in immune-oncology.


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