On the role of the purinergic receptor P2Y2R in oral cancer and salivary gland dysfunction
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Due to the important roles the oral cavity plays in our daily lives ranging from eating and drinking to speech, diseases of the oral cavity significantly impact the quality of life. Oral cancers are a subtype of head and neck cancers that mainly originate in the epithelial lining of the oral cavity. Despite the best efforts by our immune system, tumors manage to grow and destroy the surrounding tissues. Additionally, the immune system is itself capable of mediating irreparable tissue damage. The autoimmune exocrinopathy Sjogren's Disease (SjD) is one example of a disease that manifests due to aberrant immune responses. One factor that consistently appears in the study of various tumors as well as influences the immunopathology of SjD in numerous models is the G-protein coupled nucleotide receptor, P2Y2R. This metabotropic purinergic receptor is endogenously activated by extracellular ATP and UTP, and its expression has been shown in many types of tissues and cells including epithelium and immune cells. In this work, we studied the role of P2Y2Rs in the development of oral cancer tumors in vivo and examined salivary gland infiltrating immune cells in murine models of SjD and the influence of P2Y2Rs on them. To accomplish our first objective, we utilized two strategies of P2Y2R antagonism, pharmacological antagonism with the P2Y2R selective antagonist AR-C118925 and genetic ablation utilizing CRISPR-Cas9 gene editing to knock out the P2Y2R. First, we evaluated human and syngeneic murine models of head and neck squamous cell carcinoma (HNSCC) utilizing bioinformatic, genetic, and functional analyses. Second, we generated a functional P2Y2R knockout clonal MOC2 cell line and evaluated the influence of host-derived and tumor-derived P2Y2Rs in tumorigenesis in vivo. Lastly, we examined how P2Y2R expression influenced the host anti-tumor immune response. Our studies demonstrate that P2Y2R plays a role in tumor development in our murine model of oral cancer and both host- and tumor-derived expressions of P2Y2R influence the host anti-tumor immune response in distinct manners. To accomplish our second objective, we utilized three models of SjD: the NOD.H2h4, NOD.H2h4 DKO, and IL-14aTG mice. First, we conducted immunoprofiling to examine the salivary gland-accumulating leukocyte compartment of NOD.H2h4, NOD.H2h4 DKO, and age-matched C57BL/6 mice. Secondly, we isolated T lymphocytes from the salivary glands and spleens of two inflamed models of SjD, the NOD.H2h4 DKO, and the IL-14aTG models, and measured P2Y2R activity. Collectively, these works illustrate a plausible therapeutic role for antagonism of P2Y2R in oral cancer and shed light on the influence of P2Y2Rs on salivary gland accumulating T lymphocytes in SjD mouse models.
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Ph. D.