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

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.

Keywords: Granzyme B; cancer; cytotoxicity; extracellular matrix remodeling; immune response; tissue development.

Figure 1

Schematic representation of canonical and non-canonical features of Granzyme B (GzmB). (a) Targeted killing of cancer cells by T cells through granule release while inhibiting self-inflicted damage caused by leaky granules. GzmB is introduced into a target cell leading to apoptosis. GzmB leaked into T cells is inhibited by Serpin9. (b) Extracellular interaction polarizes granules for release, resulting in cleavage of extracellular factors such as fibrinogen and laminin. These cleavages increase the rate of transmigration of T cells. Serpin9 = Serine Protease Inhibitor 9.

Figure 2

Schematic representation of the novel roles of GzmB in T cell development. (Left) Mannose-6 Phosphate receptor expression orchestrates the amount of GzmB introduced into the cell, allowing for robust activation of caspase and clonal contraction. (Right) Theoretical mechanism of leaky granule release resulting in the production of IFN genes through minor DNA damage, skewing T helper frequency. IRF-3 = Interferon Regulatory Factor 3; GzmB = Granzyme B; IFN = Interferon.

Figure 3

RNAseq analysis in the coexpression of GzmB and FoxP3. (A) Relationship between GzmB and FoxP3 expression in the TCGA Pan-Cancer database, identified by UCSC Xena. Color is denoted by cancer type. (B) Kaplan–Meier survival plot of GzmB and FoxP3 gene expression extrapolated from available RNAseq data from uveal melanoma or pancreatic adenocarcinoma patients demonstrating higher GzmB expression is associated with worse survival probability. (C) Kaplan–Meier survival plot of GzmB and FoxP3 gene expression extrapolated from available RNAseq data from head and neck squamous cell carcinoma or stomach adenocarcinoma patients demonstrating higher FoxP3 and GzmB expression is associated with better survival probability.