Impact of environmental stress-induced adaptive immune responses on tissue physiology and tumorigenesis.

/ Abstract Research: It is estimated that nearly 6.5 million people in the United States suffer from chronic non-healing skin wounds. In addition, skin cancer is the most commonly diagnosed cancer in the United States. Although seemingly disparate, wound repair and tumorigenesis share many of the same molecular pathways and biological processes. In fact, tumors are often referred to as ‘wounds that don’t heal.’ Importantly, the skin must be able to repair itself and combat tumorigenesis in the context of constant exposure to detergents and other environmental factors. Yet, how environmental exposure impacts immune responses in the skin, and consequently tissue repair and tumorigenesis, remains poorly understood. Using a novel model of environmental stress, my preliminary data demonstrates that mild detergent exposure recruits IL- 17-producing CD8 T cells to the skin. I found that these CD8 T cells are specific to endogenous retroelements (ERE), germline-integrated retroviral elements. My data also demonstrate that mild detergent exposure accelerates wound repair in the skin. However, how ERE-specific CD8 T cells are recruited to and retained in the skin, and how they accelerate wound repair is unknown. Further, whether the pro-repair feature of ERE-specific CD8 T cells can be appropriated to promote tumor growth has not been explored. My overarching hypothesis is that stress-induced ERE-specific CD8 T cells are long-lived guardians of the skin barrier that support wound repair, a feature which can be hijacked to promote tumor growth. To test my hypothesis, I will use three mouse models: 1) parabiosis, to assess the recruitment and retention of ERE-specific CD8 T cells to the skin; 2) flank punch biopsy, to probe the molecular machinery that programs the pro- repair function of stress-induced CD8 T cells; and 3) transplantable cutaneous melanoma, to explore the extent to which stress-induced pro-repair CD8 T cells can promote tumor growth. Career goals: My long-term career goals are to become an independent investigator at an academic institution, where I will investigate how environmental exposure impacts the immune system and tissue physiology. Ultimately, I would like to translate this work into novel therapies and cancer prevention strategies. In addition, I aspire to be an inspirational and supportive teacher and mentor. Career development: I will meet bi-weekly with my mentor Dr. Belkaid and discuss my progress with my collaborators every 6 months for the duration of the K22 award. Prior to the K22 award, I will improve my bioinformatics and confocal microscopy skills, attend at least 2 international conferences, and attend NIH training courses (teaching, mentoring, and laboratory management workshops). Environment: The NIH Intramural Research Program has more than 1,200 PI’s conducting basic, translational, and clinical research. It is a unique environment with resources for research and career development, including immunology and cancer core facilities, as well as frequent seminars and opportunities to engage with colleagues and mentors. Prior to the K award, I will work in the laboratory of Dr. Belkaid, a BSL-2 research space adequately equipped to conduct the proposed experiments. Furthermore, I have assembled an exceptional team of collaborators and mentors that will complement my expertise in tissue immunology and wound repair (Dr. Yasmine Belkaid, Dr. Laura Mackay), and molecular immunology and anti-cancer immunity (Dr. Leonid Pobezinsky, Dr. Pamela Schwartzberg). Project Number: 1K22AI184586-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Alexandria Wells | Institution: UNIVERSITY OF PITTSBURGH AT PITTSBURGH, PITTSBURGH, PA | Award Amount: $162,000 | Activity Code: K22 | Study Section: Allergy, Immunology, and Transplantation Research Committee[AITC] View on NIH RePORTER: https://reporter.nih.gov/project-details/1K22AI18458601