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IS THIS AN OLD ONE? - Rutgers and R. Birge

Differential Phosphatidylserine sensing by TAM receptors regulates AKT dependent chemoresistance and PD-L1 expression in epithelial cells

Canan Kasikara,
Sushil Kumar and
Raymond Birge


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Author Affiliations
Microbiology, Biochemistry and Molecular Genetics, Rutgers University, Newark, NJ


Abstract

Tyro3, Axl and Mertk (TAMs) are three homologous receptor tyrosine kinases that bind vitamin K-dependent endogenous ligands, Protein S (ProS1) and Growth arrest specific factor 6 Gas6, and act as bridging molecules to promote PS-mediated clearance of apoptotic cells (efferocytosis). In recent years, it has become appreciated that TAMs are overexpressed in a vast array of tumor types, whereby the level of expression correlates with the tumor grade and the emergence of chemo and radio resistance to targeted therapeutics. TAMs have also been implicated as inhibitory receptors on infiltrating myeloid-derived cells in the tumor microenvironment that can suppress anti-tumor immunity. In addition to TAM overexpression, externalized PS is also concomitantly up-regulated in the tumor microenvironment, suggesting a PS/TAM receptor axis operates in the tumor microenvironment. Previously, we developed chimeric TAM reporter cell lines comprised of the extracellular domains of each TAM fused to the intracellular domains of the IFNR1, and reported that each TAM receptor had a unique pattern of activation by Gas6 or ProS1, as well as unique dependency for PS on apoptotic cells and PS liposomes for activity. In the present study, we leveraged this system to engineer epithelial cells that express WT TAMs, and show that while each TAM can promote PS-mediated efferocytosis, AKT-mediated chemo-resistance, as well as up-regulate the immune checkpoint inhibitory ligand PD-L1 on tumor cells, Mertk is most dominant in the aforementioned pathways. Functionally, TAM-mediated efferocytosis could be partially blocked by PS-targeted antibody 11.31 and Annexin V, demonstrating the existing of a PS/PS-R (TAM-receptor)/PD-L1 axis that operates in epithelial cells that may drive immune escape. These studies provide a rationale that anti-PS, anti-TAM, and anti-PD-L1 based therapeutics may have therapeutic merit as combinatorial checkpoint inhibitors.

Support or Funding Information

NIH CA 1650771

New Jersey Health Foundation NJHF pilot grant

Rutgers Foundation grant

http://www.fasebj.org/content/31/1_Supplement/775.10