Integrating biomaterials and genomic tools for glycan-based programming of immune cells

Project Summary/Abstract. Dendritic cells are key decision makers of the immune system and are equipped with receptors that enable them to execute molecular programs in response to foreign signals. Glycans, which bind lectin receptors on the surface of dendritic cells, can influence dendritic cell signaling to adaptive immune cells. Programmable technologies integrating glycans to direct immune cell phenotypes would be broadly useful from both a fundamental biology and a biological engineering perspective. Biomaterials such as hydrogels can present programmable molecular cues and are an ideal platform with which to study the impacts of glycans on immunity and to translate insights into clinical solutions. We will advance self-assembling modular hydrogels that programmably display glycan ligands (Aim 1). These glycomaterials will be screened for their ability to initiate maturation of innate immune cells and direct immune cell phenotypes. We will use immunophenotyping and transcriptomic readouts to screen glycomaterials for their ability to dictate immune cell phenotypes and fate decisions. In parallel, we will implement functional genomic screens in dendritic cells, generating a library of cells with impaired abilities to sense and respond to glycan ligands. We will evaluate cytokine secretion in edited cells following glycomaterial stimulation and compare to responses in wildtype cells. Thus, we will identify key regulators of glycomaterial recognition and subsequent signaling. Finally, we will use glycomaterial hydrogels as a platform for immunotherapy (Aim 3). Glycomaterials will be used to support co-culture of antigen-pulsed dendritic cells and autologous antigen- reactive T cells. We will evaluate the ability of glycan-educated immune cells to provide protection in murine models of melanoma. We anticipate that our approaches will reveal new mechanistic insights into glycobiology and how it shapes immunity. The proposed research will be carried out in the Department of Biomedical Engineering at Columbia University, under the sponsorship of Dr. Santiago Correa and Dr. Kam Leong. The expertise and facilities in this training environment will strongly enable the proposed research.