Polyamine blockade and anti-tumor immunity in head and neck squamous cell carcinoma

PROJECT SUMMARY/ABSTRACT This proposal describes a four-year Career Development Plan (CDP) to prepare R. Alex Harbison, MD to become an independent physician-scientist focused on targeting polyamine (PA) metabolism to increase immune responses to head and neck squamous cell carcinoma (HNSC). There is an urgent need to identify less toxic, targeted therapy for HNSC. Leveraging the immune system to treat HNSC is a promising approach to decrease morbidity, although the response rate is limited due, in part, to immunosuppressive PA levels in the tumor microenvironment (TME). PAs are a family of small polycations important for immune cell homeostasis. T cells require PAs for activation (i.e., via RNA translation and chromatin regulation) and differentiation (T helper subsets). However, PAs are enriched in the TME which impairs 1) anti-tumor T cell function and antigen-presentation by dendritic cells, and 2) supports immunosuppressive myeloid cells. PAs are 15-fold higher than normal in HNSC. Inhibition of both PA synthesis and uptake, known as PA blockade therapy (PBT), has dual effects on immunity. It can promote anti-tumor immune responses while also decreasing inflammation in autoimmune mouse models. Thus, the overall objective of this proposal is to define the mechanisms through which PAs modulate anti-tumor immunity. The central hypothesis is that dysregulated PA metabolism in the TME diminishes anti-tumor T cell responses which can be therapeutically targeted. The specific aims of this proposal are 1) to test mechanisms through which extracellular PAs mediate T cell responses and antigen-presentation in the TME and 2) to evaluate the effect of PBT on cos+ T cell and immune responses in the TME. The proposed studies will utilize quantitative histology and spatially resolved mass spectrometry imaging, T cell culture and co-culture with tumor cells and dendritic cells, metabolomics and carbon tracing, PA transporter knockout, and in vivo murine HNSC models to evaluate the effect of PA metabolism on anti-tumor immune responses. The mentors, Ors. Peng, Patti, and Puram, will primarily oversee the CDP providing training on immune cell signaling and development, gene knockout in primary immune cells, animal models in immunology research, and metabolomic measurements. The Research Advisory Committee will add complementary expertise in systems immunology, innate immunity and nutrient utilization, and metabolic regulation of immune function. This group is the ideal forum to chaperone the candidate's progression as a physician-scientist. The training plan includes achievement of technical expertise, grant writing skills, responsible conduct of research, and mentorship though direct experience in the lab, seminars, workshops, coursework, and presentations at national/international meetings. Immersion in the research milieu of Washington University given its extensive track record, resources, and commitment to physician-scientists provides the ideal training environment. This K08 will provide the Pl necessary skills to obtain research independence.