Identifying metabolic regulation of T cells during early childhood development

PROJECT SUMMARY/ABSTRACT Similar to the mature immune system in adults, the developing immune system in children must protect the host from infections and cancer while preventing autoimmunity. Immune system function undergoes changes during early organism development. Therefore, in order to develop appropriate immune based therapies for children requires understanding of the unique immune system features during this critical period. There is a fundamental knowledge gap in understanding the cellular mechanisms governing changes in immune system function during early life development. CD8+ T cells are critical for protection from cancer and infections and demonstrate distinct functional properties dependent upon the developmental status of the organism. Changes in cellular activity are dependent upon the support of discrete metabolic pathways (such as pyruvate) to provide energy, reducing equivalents, and biosynthetic building blocks bolstering the diverse array of cellular functions. As such, understanding how metabolic pathway usage changes over the course of early life development, within CD8+ T cells, provides a platform for mechanistically understanding T cell development. Cellular metabolism provides an investigatory approach to mechanistically probe through identifying the activity of individual metabolic pathways and their functional consequences. This allows for in situ control of immune system function via manipulation of metabolic inhibitors or donors. The impact of T cell development on these metabolic competitions in the context of pediatric cancer is unknown. Thus, understanding T cell metabolic requirements in the TME is an opportunity to enhance anti-tumor immunity and extend the benefits of immunotherapy in children with cancer. This proposal will use complementary metabolomic, transcriptomic, and cellular immunology approaches to investigate metabolic pathway activity during CD8+ T cell development and the impact on protection from the childhood cancer neuroblastoma. Using a validated immune competent preclinical model of neuroblastoma, we will mechanistically investigate the immune biology of this cancer using cellular metabolism. Our preliminary findings demonstrate T cells from young mice have increased proliferation and acquisition of effector function in response to pyruvate supplementation. Metabolically we found neonatal T cells preferentially converted pyruvate to alanine indicating a distinct developmentally regulated metabolic cellular fate. Understanding how developmental processes, like this “rewiring” of immune cell metabolism, disproportionately impacts T cell protection from cancer in young animals is critical to begin tailoring immune therapies to children. If successful aims from this proposal will determine how 1) development controls metabolic support of immune cell function, 2) organism development impacts CD8+ cell metabolic activity, and 3) metabolic regulation of anti-tumor immunity during development. While this proposal focuses on neuroblastoma, it will serve as a foundation to broadly support pediatric cancer immunotherapy discovery in other types of childhood cancers.