Improving T cell Production through Mechanometabolism and Control of Nutrient Availability

The ability of T lymphocytes, cells with key roles in adaptive immunity, to patrol the body, respond to pathogens, and coordinate activities of organs has led to their use as a “living drug”, most prominently against cancer. However, reliable manufacture of these cells remains a challenge, which has inspired the development of biomaterials that promote desirable qualities of these cells. This project focuses on using the stiffness of such materials to improve T cell production, focusing on the growing realization that the chemical composition of each material affects cell response. Specifically, this project investigates how transport of nutrients such as oxygen through biomaterials can improve T cell production and sensing of mechanical stiffness. The fundamental knowledge gained from this project will directly benefit entities involved in cell manufacturing for immunotherapy of cancer, autoimmune disease, and an ever-widening range of diseases. This project brings together mechanical engineering, biomaterials engineering, and applied immunology, and will continue to train a workforce at this diverse intersection of fields. This project also benefits from a robust commercialization environment, which will educate the next generation of researchers in not only the underlying engineering but the process of product commercialization, protecting benefits for the U.S. economy and society.The design of reactors for manufacture of living cells has major impacts on the quality and production reliability of therapeutic products. An intriguing approach to improving cell manufacturing has emerged using the ability of T cells to sense the stiffness of an activating surface; replacing the stiff materials commonly used for cell activation with mechanically softer counterparts offers more cells per round of growth and control over cell phenotype. However, the chemistry of the material affects this mechanosensing, shifting or altering this response through mechanisms that are not well understood. This project will fill this gap in knowledge by testing the role of oxygen availability, as modulated by the material, in driving T cell response. This project will use new in vitro growth configurations together with numerical simulations to test the effect of oxygen availability on a set of strategic T cell responses. The broader impact of the work includes workforce development such as the Lab-to-Market (L2M) Accelerator bootcamp will also provide training activity for students involved in this research (graduate, undergraduate, and high school students) to gain experience in translating laboratory ideas to commercial products.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.