The PD-1/PD-L1 Pathway: A Perspective on Comparative Immuno-Oncology

SIMPLE SUMMARY: The programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) pathway inhibits the function of activated immune cells. This mediates immune tolerance and prevents immune-mediated tissue destruction. The malfunction of this pathway is involved in the pathogenesis of chronic infections, autoimmunity, and cancer. The PD-1/PD-L1 pathway is an excellent example of the research benefits of comparative pathology and attests to the importance of the “one health one medicine” concept. Pioneering research was mainly focused on the examination of cells and tissues of human and mouse origin. It mainly revealed that PD-L1-positive tumor cells can paralyze PD-1-bearing immune cells, which prevents immunological destruction of cancer cells. This led to a major breakthrough in cancer treatment, i.e., the use of antibodies that block the interaction of these molecules and restore anti-cancer immune defense (immune checkpoint therapy). Further studies provided more detailed information on the tissue-specific context and fine-tuning of this pathway. The most recent research has extended the investigations to the examination of several animal species with the aim of improving disease diagnostics and treatment for certain animal diseases, in particular cancer, which is a major cause of disease and death in companion animals. ABSTRACT: The programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) pathway mainly attracted attention in immuno-oncology, leading to the development of immune checkpoint therapy. It has, however, much broader importance for tissue physiology and pathology. It mediates basic processes of immune tolerance and tissue homeostasis. In addition, it is involved in the pathogenesis of chronic infectious diseases, autoimmunity, and cancer. It is also an important paradigm for comparative pathology as well as the “one health one medicine” concept. The aim of this review is to provide an overview of novel research into the diverse facets of the PD-1/PD-L1 pathway and to give insights into its fine-tuning homeostatic role in a tissue-specific context. This review details early translational research from the discovery phase based on mice as animal models for understanding pathophysiological aspects in human tissues to more recent research extending the investigations to several animal species. The latter has the twofold goal of comparing this pathway between humans and different animal species and translating diagnostic tools and treatment options established for the use in human beings to animals and vice versa.