Project 4- Dr. Thomas Werfel
Efferocytosis, the phagocytic clearance of apoptotic cells, in the tumor microenvironment promotes immunosuppression, dampening tumor immunogenicity and thus the therapeutic response to cytotoxic and immunotherapies. Macrophages are primarily responsible for efferocytosis in the tumor microenvironment, where they recognize apoptotic cells using the phosphatidylserine receptor MerTK and then produce a host of immunosuppressive signals in response to apoptotic cell engulfment. Attempts to block efferocytosis in the tumor microenvironment by inhibiting the activity of MerTK show promise. However, chronic, systemic blockade of MerTK and/or hypomorphic MerTK mutations contribute to inflammation-related retinopathies, lupus-like auto-immunity, and risk of auto-immunity. To circumvent the deleterious effects of auto-immunity associated with chronic systemic inhibition, we propose to target MerTK specifically within tumor-associated macrophages (TAMs) using high-mannose decorated-nanoparticles (hmNPs) harboring a MerTK inhibitor. We propose novel synthetic strategies to produce hmNPs with 1) a polypropylene sulfide core for hydrophobic drug loading and 2) a glycopolymer-based corona consisting of a mixture of trehalose and mannose polymers. Trehalose has been shown to impart enhanced stability to drug delivery vehicles and will be crucial for endowing the stability necessary for systemic delivery applications. Mannose decoration has been used as a strategy to target nanoparticles to TAMs because of their characteristic overexpression of the mannose receptor. However, past strategies have been limited to local delivery applications and/or have employed carriers not suited for hydrophobic drug loading.
The design proposed herein will enable encapsulation, intravenous administration, and macrophage-specific targeting of small molecules that inhibit MerTK (e.g. UNC2025). Moreover, the polymeric version of mannose is designed to closely mimic the natural binding partners for mannose receptor, mannan and high-mannose glycans, which have much higher affinity for the receptor than monomeric mannose. Using the TAM-targeting hmNPs as an enabling technology, we will test the therapeutic impact of TAM-specific MerTK inhibition on immunosuppression in the tumor microenvironment, tumor progression, and systemic auto-immunity. Importantly, this will be, to our knowledge, the first attempt to develop a therapy that preferentially inhibits efferocytosis within the tumor microenvironment, underscoring the high risk/high reward nature of the project and potential to develop a unique, new class of anti-efferocytic cancer immunotherapies.
Thomas Werfel is an Assistant Professor of Biomedical Engineering, Chemical Engineering, and BioMolecular Sciences at The University of Mississippi, a position he began in the fall of 2018. Dr. Werfel received his PhD in Biomedical Engineering in 2017 from Vanderbilt University under the dissertation direction of Dr. Craig Duvall. He then transitioned to Vanderbilt University School of Medicine for a postdoctoral research position in Cell and Development Biology. Dr. Werfel’s current interdisciplinary research program at The University of Mississippi leverages tools from bioengineering, cancer biology, and translational science to engineer novel therapies that disrupt cancer progression, recurrence, and metastasis.