Harnessing immune-epithelial interactions to promote restoration of salivary gland function after IR

More than 73% of head and neck cancer patients continue to suffer from the chronic consequences of xerostomia months to years after the completion of radiotherapy making this one of the most compelling issues in salivary gland biology. Despite technological advancements in cancer therapies, collateral damage to salivary glands remains a significant problem for these patients and severely diminishes their quality of life. The field of radiation- induced salivary gland damage is severely hampered by the lack of a comprehensive model detailing the molecular stages of damage. The overall vision (long-term goal) is to restore salivary gland function in patients following radiotherapy by identifying mechanisms that regulate stages of dysfunction in salivary glands. Our prior work has demonstrated that mouse parotid glands 10 months after fractionated radiation have significant increases in T cell populations (CD4+, CD8+, CD4+CD8+, and FoxP3+ T cells), suggesting immune populations may play an active role in the chronic loss of salivary gland function. We hypothesize that radiation treatment leads to chronic dysregulation of metabolic pathways in T cells resulting in prolonged activation of CD4+CD8+, double positive (DP) T cells that inhibit salivary epithelial regeneration and repair. We propose to develop a kinetic model of the metabolic phenotype of infiltrating immune populations and how immune-epithelial interactions contribute to chronic loss of function. The outcomes from this work include: 1) immunometabolic phenotype and the function of T cells following radiation, 2) the effect of modulating T cell metabolism on repair of damaged glands, 3) cellular identity of immune populations surrounding damaged epithelial cells, 4) impact of immune cell metabolic phenotype on the ability of Metformin to reverse salivary gland dysfunction. Understanding this process would have a positive impact by revealing intervention points that promote restoration of salivary gland function. Project Number: 1R01DE034985-01 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Dental and Craniofacial Research (NIDCR) | Principal Investigator: KIRSTEN LIMESAND | Institution: UNIVERSITY OF ARIZONA, TUCSON, AZ | Award Amount: $644,970 | Activity Code: R01 | Study Section: Oral, Dental and Craniofacial Sciences Study Section[ODCS] View on NIH RePORTER: https://reporter.nih.gov/project-details/11163112