ENGINEERING MATERIALS FOR IMMUNOMODULATION

Abstract

The development of materials-based immune organs and scalable technologies are emerging fields within a broader field of immune engineering, aiming to transform the fundamental knowledge of the immune system and provide therapeutic solutions for the treatment of infection, cancer, inflammatory diseases, and age-related malfunctions. Technologies that enable ex vivo generation of immune cells for immunotherapy are already in high demand, however, only a few scalable technologies for immune cell generation exist. At the same time, current immune-therapeutic treatments do not work across a broad range of disorders, causes of which are poorly understood. Likewise, most antigen discovery and vaccine development rely on mouse immunizations or isolation of monoclonal antibodies from infected patients. The challenge ahead is establishing how best to develop cell-based or cell-free immune-therapeutics promptly or to understand the precise factors that regulate signaling in immune cells to develop new classes of small molecule inhibitors.In order to address these limitations, we engineered materials for lymphocyte modulations. We first highlight the potential for materials science to greatly contribute to immune cell and tissue engineering (Chapter 1). This investigation includes the potential development of dynamic, stimuli-responsive, and context-dependent materials to more effectively model and engineer immune cells at the cell, tissue, and organ level. For regulating immune cell fates and engineering lymphocytes, we developed the novel nanowire device for delivering genetic materials and immuno-modulating naïve CD8+ T cells (Chapter 2). Engineered CD8+ T cells were programmed to induce robust effector immune characteristics and demonstrated significant regression of melanoma tumors with the presence of tumor-infiltrating lymphocytes (TIL), in vitro and in vivo (Chapter 3). Inspired by the role of mechanical support in the cell microenvironment, we utilized the polyethylene glycol-maleimide (PEG-MAL) hydrogels, which exploited both covalent and ionic conjugations to display reversibility and stiffness controllability and investigated mechanical force-dependent germinal center (GC)-like B cell expansion in culture (Chapter 4). We next developed immune organoids to recapitulate temporal GC signaling by controlling the presence and depletion of key signals for B cell activation (Chapter 5). Having described the works done to develop improved microenvironments for B cell activations and device platform for T cell immunomodulation, we concluded this dissertation with a reflection on the research journey and some suggestions regarding the next key steps to continue these topics (Chapter 6). In the long term, we believe that the immune organoid and functionalized nanowire platform could be used to obtain mechanistic insights about the adaptive immune system generation, understand the key-making process in GC reaction, manufacture tumor or disease-specific effector T cells, and enable ex vivo or in vitro generation of engineered immune cells for immunotherapy.