Sex-specific immune microenvironment in oral cancer

/ Abstract Head and neck squamous cell carcinoma (HNSCC) is an aggressive cancer affecting the mucosal linings of the nose and mouth and is associated with smoking, alcohol consumption and HPV infection. Surgery and radiation targeted to the face of cancer patients comes with significant morbidities such as difficulty swallowing, dry mouth, loss of musculature and deformities. The rate of HNSCC is 2.7-times higher in men than women, but is insufficiently attributed to tobacco usage, alcohol consumption or rates of HPV infection suggesting that biological differences between the two sexes contribute to HNSCC. Thus, determining the sex-specific drivers of HNSCC including sex-specific drivers of the immune microenvironment is a critical component to advance precision medicine, matching patients with rational therapies to alleviate patient suffering. Because human patient data demonstrate a critical difference in HNSCC rates in men versus women, the use of animal models of HNSCC will allow us to directly test sex as a biological variable independent of unavoidable, human-related variables. Our preliminary data demonstrate that identical tumors transplanted in male and female immune competent mice grow more quickly in male recipients, tumors in female mice have increased cytotoxic CD8 T cells and monocytes, and tumors in male mice have elevated neutrophils. In our recent publication we demonstrated that neutrophils from tumor-bearing mice possess immunosuppressive activity of myeloid-derived suppressor cells (MDSCs) that inhibit CD8+ T cell activity and promote tumor survival. These data lead us to the hypothesis that sex-specific HNSCC aggressiveness is due, in part, to sex-specific myeloid cell differences in male vs female patients. We will test this hypothesis in the following specific aims: Aim 1: Determine sex-specific myeloid cell differences and activities in transplant models of HNSCC in male and female immune competent mice. Aim 2: Determine sex-specific consequences that deleting PMNs has upon oral tumor progression and the tumor immune microenvironment. Aim 3: Determine the sex-specific myeloid cell microenvironment of human oral cancer specimens. Completing these aims will determine how the immune microenvironment differs in male vs female HNSCCs and the relative contribution of PMNs to tumorigenesis and CD8 T cell activity in males vs females. Establishing these models and collecting these preliminary data will allow us to propose future, mechanistically focused aims in future R01 applications. These studies are critical to our long-term goal to identify cellular and molecular mechanisms that mediate oral malignancy that can then serve as biomarkers and/or targets for personalized therapy to prevent malignancy or more precisely treat patients to improve quality of life. Project Number: 1R03DE034748-01 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Dental and Craniofacial Research (NIDCR) | Principal Investigator: Christian Young | Institution: UNIVERSITY OF COLORADO DENVER, Aurora, CO | Award Amount: $156,000 | Activity Code: R03 | Study Section: Special Emphasis Panel[ZDE1 TO (04)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11116382