Emerging Canonical and Non-Canonical Roles of Granzyme B in Health and Disease

SIMPLE SUMMARY: Granzyme B (GzmB) is a potent cytotoxic molecule that is used by cytotoxic T lymphocytes and natural killer cells to kill targeted infected or cancerous cells. Since its discovery, there has been growing evidence showing more roles besides cell death such as tissue development and repair. Recent developments in the study of GzmB have given scientists the opportunity to bridge the concepts of cytotoxicity and development, showing that its expression, secretion and function are more intricate than originally suggested. In this review, we provide an overview of the emerging knowledge of GzmB, both canonical and non-canonical, and how these features can be used to elucidate our understanding of GzmB under different clinical conditions. ABSTRACT: The Granzyme (Gzm) family has classically been recognized as a cytotoxic tool utilized by cytotoxic T lymphocytes (CTL) and natural killer (NK) cells to illicit cell death to infected and cancerous cells. Their importance is established based on evidence showing that deficiencies in these cell death executors result in defective immune responses. Recent findings have shown the importance of Granzyme B (GzmB) in regulatory immune cells, which may contribute to tumor growth and immune evasion during cancer development. Other studies have shown that members of the Gzm family are important for biological processes such as extracellular matrix remodeling, angiogenesis and organized vascular degradation. With this growing body of evidence, it is becoming more important to understand the broader function of Gzm’s rather than a specific executor of cell death, and we should be aware of the many alternative roles that Gzm’s play in physiological and pathological conditions. Therefore, we review the classical as well as novel non-canonical functions of GzmB and discuss approaches to utilize these new findings to address current gaps in our understanding of the immune system and tissue development.