Cellular and microenvironmental mechanisms linking aging to tumor control

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Project Summary. Research. Cancer incidence increases dramatically with age. While the average life expectancy continues to rise, one consequence is that cancer cases are predicted to grow by 45% between 2010 and 2030, highlighting the critical need to study the intersection between aging physiology and tumorigenesis. However, the majority of cancer research is performed using young adult mice as pre-clinical cancer models, where impact of environmental risk factors, like aging, on key features of tumorigenesis cannot be measured. The immune system is especially vulnerable to functional decline with aging. Many different kinds of immune cells can be found infiltrating tumors, where CD8+ T cells in particular can identify and selectively kill cancer cells by recognizing tumor features that differ from normal tissue. Although studies have shown that aging diminishes CD8+ T cell proliferation and effector responses following bacterial and viral infections, the role of aging on anti- tumor immunity is still a major black box. Based on our preliminary data in tumors from young and aged mice, we hypothesize that impaired anti-tumor immunity by CD8+ T cells contributes to tumorigenesis during aging. To test this hypothesis, Aim 1 will first develop mouse models to study aging, cancer, and anti-tumor immunity, and then identify mechanisms that alter immune cell function in the tumor niche using flow cytometry and single cell RNA-sequencing. In Aim 2, we will define metabolic changes in the aged tumor microenvironment and then test whether these are causal for CD8+ T cell dysfunction. Finally, Aim 3 will determine whether enhancing metabolic pathways in immune cells identified by transcriptomic and metabolomic analysis can improve tumor control during aging. By revealing how the tumor microenvironment changes with age and the impact on anti-tumor immunity, these studies will identify mechanisms that drive T cell dysfunction in tumors that may be targeted to improve cancer prevention and therapy. Candidate. Dr. Alison Ringel, PhD, is the PI for this research proposal. She has worked as a postdoctoral fellow for the past five years at Harvard Medical School, where she has sought to understand the molecular mechanisms that drive tumorigenesis in response to environmental cancer risk factors such as obesity. She is in the process of interviewing for tenure-track faculty positions and has mapped out a detailed professional development plan that will enable her to transition to an independent research career where she will develop her research program on aging and tumorigenesis. She aims to become a leader in cancer immunology by applying an innovative systems biology approach to dissect the tumor niche, which will distinguish her independent work from that of her postdoctoral mentors. Her long-term goal is to lead an independent cancer research program dedicated to the discovery of molecular mechanisms within tumors that regulate local immune responses and tumor progression.