The Role of Nanoparticles in Cancer Therapy through Apoptosis Induction
Hala Gali-Muhtasib, Racha Chouaib in Nanoparticle Drug Delivery Systems for Cancer Treatment, 2020
When cells are infected by viruses, the perforin/granzyme apoptosis pathway is initiated by cytotoxic lymphocytes to remove the infected cells. Perforin, also known as cytoplasmic granule toxin, is a kind of protein with a pore-forming ability in mitochondrial membrane. Granzyme is a serine protease protein, which contains cytotoxic granules of cytotoxic lymphocytes (CLs). Although, Granzyme is required for triggering apoptosis, it should be delivered appropriately by perforin. In humans, there are numerous granzymes including A, B, H, K, and M, but the Granzymes A and B are the most abundant enzymes that are involved in apoptosis. This pathway is initiated when granzymes could enter into target cells. This internalization is facilitated by perforin. Granzyme B activates pro-apoptotic BH3-interacting domain death agonist Bid, leading to the activation of CASP-3. Activated CASP-3 is subsequently able to proceed with executive apoptosis. Granzyme B can also inactivate MCL-1, which is a member of the anti-apoptotic BCL-2 family [36]. The granzyme A pathway is also involved in apoptosis via activating a parallel, caspase-independent cell death pathway through single-stranded DNA damage [37].
Adenoviruses
Dongyou Liu in Laboratory Models for Foodborne Infections, 2017
One of the nonstructural proteins is encoded by L4 gene. The L4-100-kDa protein inhibits the translation of cellular mRNA by eliminating the cap-dependent translation pathway via binding to eukaryotic initiation factor 4G (eIF4G) and displacing Mnk1 from eIF4G. It also promotes translation of late viral mRNAs through ribosome shunting, which leads to nuclear accumulation of viral products for capsid assembly. The underlying mechanism for these functions is the interaction of L4-100 kDa with the tripartite leader (TL) sequence present in all the late viral transcripts and eIF4G, which is the scaffolding element of the cap-dependent translation initiation complex. In addition, L4-100-kDa protein not only acts as a chaperone facilitating hexon trimerization but also assists in nuclear accumulation of hexon trimers and in the scaffolding process of AdV capsid.98–101 Another function of L4-100 kDa is to prevent apoptosis induced by granzyme B in infected cells. Granzyme B, one of the lymphocyte granule serine proteases, catalyzes the cleavage and activation of several caspases which induce apoptotic events in infected cells. By interacting with granzyme B, the L4-100-kDa protein prevents access of substrates to the proteinase catalytic site through steric hindrance and inhibits its activity.102 A unique feature of L4-100 kDa is its posttranslational modification by arginine methyltransferase 1 (RPMT1). The methylation of L4-100 kDa has regulatory effects on modulating its interaction with hexon and TL mRNA as well as on promoting the capsid assembly.101
Acquired Immunity
Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal in Principles of Physiology for the Anaesthetist, 2020
The other one-third of T lymphocytes are called cytotoxic T lymphocytes. They have the CD8 surface glycoprotein and interact with peptides presented by MHC class I molecules on cells (Figure 56.8). Cytotoxic T cells kill other cells by perforins into target cell membranes through which granzyme is inserted, resulting in osmotic lysis of the cell or by inducing apoptosis via activation of caspases. These actions are used in controlling viral infections and cancers. Cytotoxic T lymphocytes also secrete the cytokines IFN-γ, IL-2, TNF and lymphotoxin (Figure 56.9).
Predictive role of plasmatic biomarkers in advanced non-small cell lung cancer treated by nivolumab
Published in OncoImmunology, 2018
Adrien Costantini, Catherine Julie, Coraline Dumenil, Zofia Hélias-Rodzewicz, Julie Tisserand, Jennifer Dumoulin, Violaine Giraud, Sylvie Labrune, Thierry Chinet, Jean-François Emile, Etienne Giroux Leprieur
Granzyme B is a serine protease that is a mediator of target-cell apoptosis by cells such as NK cells and cytotoxic CD8+ T cells. Granzymes are delivered to the target cells via cytotoxic granules and are responsible for caspase-dependant apoptosis.24,25 Soluble Granzyme B has already been explored in the context of auto-immune diseases, showing that high levels of sGran B were associated with rheumatoid arthritis, myocardial infarction and lipid-rich carotid plaques.26-28 To our knowledge, this is the first time that sGran B concentrations have been evaluated in the plasma of NSCLC patients treated with nivolumab. We found that patients who presented with an objective response to nivolumab had significantly higher sGran B concentrations at nivolumab initiation than patients who were non-responders. This could reflect the activation of the CD8+ cytotoxic immune response, known to be associated with better response with ICIs. When analysing the variation of sGran B concentrations between nivolumab initiation and first tumour evaluation we found a tendency favouring patients with stable or decreasing concentrations for ORR, clinical benefit, OS and PFS. As for sPD-L1, an increase of sGran B at the beginning of the treatment could be the reflection of the persistence of a high tumour volume, with persistent CD8 lymphocytes activation and Granzyme B secretion. However, these hypotheses need to be validated in further studies.
Granzyme B as a therapeutic target for wound healing
Published in Expert Opinion on Therapeutic Targets, 2019
Christopher T. Turner, Sho Hiroyasu, David J. Granville
The ability of granzyme B to act both intracellularly and extracellularly in skin suggests it may contribute to impaired wound healing and skin pathogenesis via multiple mechanisms. This is likely dependent on the context and where and when granzyme B is produced. Experiments to identify the underlying mechanisms of granzyme B in wound repair and inflammatory disease have previously been performed using perforin knockout mice [52]. As such, study outcomes were limited to the perforin-dependent roles for granzyme B and did not consider potential extracellular roles. One study by Chamberlain et al. compared granzyme B and perforin knockout mice using a model of abdominal aortic aneurysm, displaying increased survival and a decrease of aneurysm in granzyme B but not perforin knockdown [53]. The latter use of granzyme B knockout mice therefore facilitated significant progress to be made in elucidating the underlying mechanisms of extracellular granzyme B in wound injury and repair [43,54,55].
Immunotoxins and nanobody-based immunotoxins: review and update
Published in Journal of Drug Targeting, 2021
Mohammad Reza Khirehgesh, Jafar Sharifi, Fatemeh Safari, Bahman Akbari
For further deimmunising, human endogenous cytotoxic enzymes such as Granzyme B and RNase have been used in IT development. Granzyme B secretes from activated cytotoxic T-cells and natural killer cells. Translocation of Granzyme B into target cells leads to apoptosis induction [121–124]. Another strategy to reducing the immunogenicity of ITs is PEGylation, attaching polyethylene glycol to the target molecules. However, ITs PEGylation leads to reduced binding affinity and increased size [125,126]. Vascular leak syndrome (VLS) is one of the common side effects and dose-limiting toxicity of ITs. VLS is characterised by increased vascular permeability accompanied by extravasation of fluids and proteins, resulting in interstitial edoema and organ failure [127]. The conserved motif exists in RTA, PE and IL2 that induces VLS via binding to the endothelial cells [128]. Removing the motif may prevent VLS induction in IT therapy.