Dog oral melanoma, transcriptome, Immune landcape. Single Institution Study of the Immune Landscape for Canine Oral Melanoma Based on Transcriptome Analysis of the Primary Tumor

Understanding a tumor’s immune context is paramount in the fight against cancer. Oral melanoma in dogs serves as an excellent translational model for human immunotherapy. Advanced studies are necessary to comprehend the immune landscape of this tumor, including the analysis of immune cell density, locations within the tumor, function, and interaction with the microenvironment. This retrospective study utilizes bulk tissue samples to analyze RNA sequences associated with oral melanoma in dogs. The focus is on understanding the differences between primary tumors restricted to the oral cavity (OL) and those known to have metastasis to the lymph nodes or other organs (OM). In the OM patient group, gene signatures in melanoma exhibit changes such as a decrease in biomarkers S100, an increase in Sox 10, heightened cell division activity (KI-67), Kit expression, reduced suppressors genes (P63, DMTB1), and increased hypoxia (VEGFA expression). Moreover, the preliminary analysis of the immune landscape in the OM group indicates a shift from a possible “hot” tumor suppressed by immune checkpoints, CTLA4 and PDL1, to a heightened expression not only of those checkpoints but also the inclusion of another immune blockade such as PD1, IDO1, IDO2. Additionally, evidence of immune cell exhaustion is evident by RNA biomarkers (TIGIT, LAG3) and lower expression of PDL2. The OM group also shows fewer immune cell effectors (CD4, pro-immune macrophages) within the immune landscape. Reduced TLR diminished IL-2, IL15, and IL-18, along with secretions of immunosuppressive chemokines (IL-6 and IL13), contribute to the tumor's immune escape. The level of interferon secretions (Beta1 and Gamma) is weak, signaling the absence of T effectors priming and activation. To counter the immunosuppressed condition in advanced patients, targeting immune checkpoints or the microenvironment (hypoxia, suppressive chemokines) could be viable therapeutic strategies. Other options could include the administration of TLR agonists, interleukins (IL-2, IL-15) in combination with vaccination, or radiation therapy. However, those hypothesis needs verification through in-depth pathology analysis. Additionally, conducting massive real-time PCR analysis could significantly contribute to categorizing the immune landscape for this neoplasia.