Tyro3, Axl and Mer (TAMs) are three homologous receptor tyrosine kinases that bind vitamin K-dependent endogenous ligands, Protein S (PROS1) and Gas6, and act as bridging molecules to promote PS-mediated clearance of apoptotic cells (efferocytosis). In recent years, evidence has accumulated that TAMs are overexpressed in a wide 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 myeloid-derived cells that suppress anti-tumor immunity. In addition to TAM overexpression, externalized PS is also concomitantly up-regulated in the tumor microenvironment, suggesting that PS and PS receptors might act as immune checkpoint inhibitors. To better understand the biology of TAMs, and the specificity of interaction between TAMs and PS, we generated chimeric TAM reporter cell lines comprised of the extracellular domains of each TAM fused to the intracellular domains of the IFNR1, as well as cell lines stably expressing full-length native TAMs. Using these systems, we found that each TAM receptor has a unique pattern of activation by GAS6 and PROS1, as well as unique dependency for PS on apoptotic cells, PS liposomes, and exosomes. Interrogating epithelial cells that express WT TAMs, we also observed that each TAM showed differential capacity for efferocytosis, AKT-mediated chemo-resistance, and their ability to up-regulate the immune checkpoint inhibitory ligand PD-L1 on breast cancer cells. Functionally, TAM-mediated efferocytosis and PD-L1 up-regulation could be partially blocked by PS targeted antibodies 11.31 and bavituximab, suggesting the existence of a PS/PS-R (TAM-receptor)/PD-L1 axis that drives immune escape in solid cancers. These studies demonstrate that, despite their similarities, Tyro3, Axl and Mertk are likely to perform distinct functions in both immune-regulation and the recognition and removal of apoptotic cells. Finally, these studies provide a rationale for combinatorial therapeutics targeting PS, TAM, and PD-L1 as immune checkpoint inhibitors in the treatment of cancer.
Citation Format: Canan Kasikara, Sushil Kumar, Ke Geng, Viral Davre, Cyril Empig, Bruce Freimark, Michael Gray, Kyle Schlunegger, Jeff Hutchins, Sergei V. Kotenko, Raymond B. Birge. Characterization of a phosphatidylserine, TAM receptor (Tyro3, Axl, Mertk), PDL1 axis in breast cancer [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B119.
- ©2016 American Association for Cancer Research.