Canan Kasikara

Molecular Biologist

About Me

I am a scientist at Regeneron Pharmaceuticals. I completed my post-doctoral studies in Tabas Lab at the Columbia University. I received my Bachelor of Science Degree from Bilkent University in 2011. I then received my Ph.D. degree in Molecular Biology, Genetic and Cancer from Rutgers University. Working in the laboratory of Dr. Raymond B. Birge, my Ph.D. studies focused on the role of TAM receptors in epithelial cell efforocytosis and tumor immune evasion. I joined the Tabas laboratory in December 2017 with an interest in understanding how insulin resistance and atherosclerosis are linked in the perceptive of MerTK-dependent efferocytosis and inflammation resolution signaling.

Research

Pan-TAM tyrosine kinase inhibitor BMS-777607 enhances anti–PD-1 mAb efficacy in a murine model of triple-negative breast Cancer

Canan Kasikara, Viralkumar Davra, David Calianese, Ke Geng, Thomas E Spires, Michael Quigley, Michael Wichroski, Ganapathy Sriram, Lucia Suarez-Lopez, Michael B Yaffe, Sergei V Kotenko, Mariana S De Lorenzo, Raymond B Birge

Abstract: Tyro3, Axl, and Mertk (TAM) represent a family of homologous tyrosine kinase receptors known for their functional role in phosphatidylserine (PS)-dependent clearance of apoptotic cells and also for their immune modulatory functions in the resolution of inflammation. Previous studies in our laboratory have shown that Gas6/PS-mediated activation of TAM receptors on tumor cells leads to subsequent upregulation of PD-L1, defining a putative PS!TAM receptor!PD-L1 inhibitory signaling axis in the cancer microenvironment that may promote tolerance. In this study, we tested combinations of TAM inhibitors and PD-1 mAbs in a syngeneic orthotopic E0771 murine triple-negative breast cancer model, whereby tumor-bearing mice were treated with pan-TAM kinase inhibitor (BMS-777607) or anti–PD-1 alone or in combination. Tyro3, Axl, and Mertk were differentially expressed on multiple cell subtypes in the tumor microenvironment. Although monotherapeutic administration of either pan-TAM kinase inhibitor (BMS-777607) or anti– PD-1 mAb therapy showed partial antitumor activity, combined treatment of BMS-777607 with anti–PD-1 significantly decreased tumor growth and incidence of lung metastasis. Moreover, combined treatment with BMS-777607 and anti–PD-1 showed increased infiltration of immune stimulatory T cells versus either monotherapy treatment alone. RNA NanoString profiling showed enhanced infiltration of antitumor effector T cells and a skewed immunogenic immune profile. Proinflammatory cytokines increased with combinational treatment. Together, these studies indicate that pan-TAM inhibitor BMS-777607 cooperates with anti–PD-1 in a syngeneic mouse model for triple-negative breast cancer and highlights the clinical potential for this combined therapy.

The role of non-resolving inflammation in atherosclerosis

Canan Kasikara, Amanda C Doran, Bishuang Cai, Ira Tabas

Abstract: Non-resolving inflammation drives the development of clinically dangerous atherosclerotic lesions by promoting sustained plaque inflammation, large necrotic cores, thin fibrous caps, and thrombosis. Resolution of inflammation is not merely a passive return to homeostasis, but rather an active process mediated by specific molecules, including fatty acid–derived specialized pro-resolving mediators (SPMs). In advanced atherosclerosis, there is an imbalance between levels of SPMs and proinflammatory lipid mediators, which results in sustained leukocyte influx into lesions, inflammatory macrophage polarization, and impaired efferocytosis. In animal models of advanced atherosclerosis, restoration of SPMs limits plaque progression by suppressing inflammation, enhancing efferocytosis, and promoting an increase in collagen cap thickness. This Review discusses the roles of non-resolving inflammation in atherosclerosis and highlights the unique therapeutic potential of SPMs in blocking the progression of clinically dangerous plaques.

Phosphatidylserine sensing by TAM receptors regulates AKT-dependent chemoresistance and PD-L1 expression

Canan Kasikara, Sushil Kumar, Stanley Kimani, Wen-I Tsou, Ke Geng, Viralkumar Davra, Ganapathy Sriram, Connor Devoe, Khanh-Quynh N Nguyen, Anita Antes, Allen Krantz, Grzegorz Rymarczyk, Andrzej Wilczynski, Cyril Empig, Bruce Freimark, Michael Gray, Kyle Schlunegger, Jeff Hutchins, Sergei V Kotenko, Raymond B Birge

Abstract: Tyro3, Axl, and Mertk (collectively TAM receptors) are three homologous receptor tyrosine kinases 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 correlates with the tumor grade and the emergence of chemoand radioresistance to targeted therapeutics, but also have been implicated as inhibitory receptors on infiltrating myeloidderived cells in the tumor microenvironment that can suppress host antitumor immunity. In the present study, we utilized TAM-IFNgR1 reporter lines and expressed TAM receptors in a variety of epithelial cell model systems to show that each TAM receptor has 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 wild-type TAM receptors and show that although each receptor can promote PS-mediated efferocytosis, AKT-mediated chemoresistance, as well as upregulate 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 receptor (i.e., TAM receptor)/PD-L1 axis that operates in epithelial cells to foster immune escape. These data provide a rationale that PS-targeting, anti–TAM receptor, and anti–PD-L1-based therapeutics will have merit as combinatorial checkpoint inhibitors.

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

Canan Kasikara, Sushil Kumar, and Raymond Birge

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.

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