Breed-Associated Differences in Differential Gene Expression Following Immunotherapy-Based Treatment of Canine High-Grade Glioma.

Simple Summary: Canine high-grade glioma (HGG) is a deadly disease in dogs, with limited treatment options. Involving the host immune system in the fight against HGG through immunotherapy has improved outcomes in many dogs, with a notable exception in the French bulldog breed. We hypothesized that French bulldog HGG responds differently to immunotherapy than other breeds, and that this response difference is attributable to differences in transcriptomic landscapes in the breed compared to other breeds. We performed bulk RNA sequencing (RNASeq) on tumors pre-treatment and post-treatment and examined the differentially expressed genes (DEGs) between the two timepoints in both French bulldogs and in our comparison group of boxers and Boston terriers. We then analyzed the differences in DEGs between French bulldogs and boxers and Boston terriers, and performed gene set enrichment analysis (GSEA) to categorize the observed changes by gene function. We confirmed that when compared to boxers and Boston terriers, the transcriptomes of French bulldog tumors change in significantly different ways following immunotherapy treatment, with many DEGs mapping to tumor-promoting pathways and immune pathways. This study highlights important breed-associated differences in HGG transcriptomes, which may guide patient-centered immunotherapy treatment to improve patient outcomes. Canine high-grade glioma (HGG) is among the deadliest and most treatment-resistant forms of canine cancer. Successful, widespread treatment is challenged by heterogeneity in tumor cells and the tumor microenvironment and tumor evolution following treatment. Immunotherapy is theoretically a strong novel therapy, since HGG-generated immunosuppression is a substantial malignancy mechanism. Immunotherapy has improved survival times overall, but has been associated with extremely poor outcomes in French bulldogs. Given this breed-specific observation, we hypothesized that within the French bulldog breed, there are key transcriptomic differences when compared to other breeds, and that their tumors change differently in response to immunotherapy. Using bulk RNA sequencing, French bulldog tumors were confirmed to differ substantially from boxer and Boston terrier tumors, with only 15.9% overlap in significant differentially expressed genes (DEGs). In upregulated DEGs, the magnitude of changes in expression post-treatment compared to pre-treatment was markedly greater in French bulldogs. Gene set enrichment analysis confirmed that following treatment, French bulldog tumors showed enrichment of key immune-associated pathways previously correlated with poor prognosis. Overall, this study confirmed that French bulldog HGG transcriptomes differ from boxer and Boston terrier transcriptomes, further refining description of the canine glioma transcriptome and providing important information to guide novel therapy development, both for specific dog breeds and for possible correlative variants of human glioblastoma. [ABSTRACT FROM AUTHOR]