The PD-1 / PD-L1 pathway: possible immunotherapeutic target in canine urothelial carcinoma

Abstract

Canine urothelial carcinoma (UC) is the most common genitourinary tumour described in dogs. Despite the multitude of therapies attempted over the last decade, there continues to be a need for new and novel therapies to improve treatment response and overall survival. Additionally, given the advent of immunotherapy and checkpoint inhibitors in human muscle-invasive urothelial carcinoma, there remains a gap in knowledge regarding the immune landscape of canine urothelial carcinoma, especially pertaining to the programmed death ligand (PD-L1) and its receptor (PD-1). The present works evaluated three UC cell lines and documented protein and mRNA expression of both PD-1 and PD-L1 in all lines. In a group of canine patients with urothelial carcinoma, when compared to healthy control dogs, the CD8+ T lymphocyte expression of PD-1 was significantly elevated. Decreased CD8:Treg ratios were documented in the urine of UC patients, supportive of an immunosuppressive environment. Lastly, cytokines implicated in the upregulation of PD-1 were significantly elevated in UC patients when compared to healthy control dogs. This thesis provides evidence of tumour cell line- based expression of PD-1 and PD-L1, as well as the lymphocyte-specific expression of PD-1 in dogs with urothelial carcinoma. Therefore, we conclude that immune checkpoint therapy against PD-1 and/or PD-L1 should be further explored as a relevant therapeutic strategy in dogs with urothelial carcinoma.