Tumoral P2Y2 receptor modulates tumor growth and host anti-tumor immune responses in a syngeneic murine model of oral cancer.

Head and neck squamous cell carcinomas (HNSCCs) are a heterogenous group of tumors and among the top 10 most common cancers and they arise from the epithelial tissues of the mucosal surfaces of the oral cavity, oropharynx, and larynx. Aberrant purinergic signaling has been associated with various cancer types. Here, we studied the role of the P2Y₂ purinergic receptor (P2Y₂R) in the context of oral cancer. We utilized bioinformatics analysis of deposited datasets to examine purinome gene expression in HNSCC tumors and cells lines and functionally characterized nucleotide-induced P2 receptor signaling in human FaDu and Cal27 and murine MOC2 oral cancer cell lines. Utilizing tumorigenesis assays with wild-type or P2ry2 knockout MOC2 cells we evaluated the role of P2Y₂Rs in tumor growth and the host anti-tumor immune responses. Our data demonstrate that human and murine oral cancer cell lines express numerous P2 receptors, with the P2Y₂R being highly expressed. Using syngeneic tumor grafts in wild-type mice, we observed that MOC2 tumors expressing P2Y₂R were larger than P2Y₂R^-/- tumors. Wild-type MOC2 tumors contained a lower population of tumor-infiltrating CD11b⁺F4/80⁺ macrophages and CD3⁺ cells, which were revealed to be CD3⁺CD4⁺IFNγ⁺ T cells, compared to P2Y₂R^-/- tumors. These results were mirrored when utilizing P2Y₂R^-/- mice, indicating that the changes in MOC2 tumor growth and to the host anti-tumor immune response were independent of host derived P2Y₂Rs. Results suggest that targeted suppression of the P2Y₂R in HNSCC cells in vivo, rather than systemic P2Y₂R antagonism, may be a more effective treatment strategy for HNSCCs.