Expression of the granzyme B inhibitor, protease inhibitor 9, by tumor cells in patients with non-Hodgkin and Hodgkin lymphoma: a novel protective mechanism for tumor cells to circumvent the immune system?

Bladergroen, Bellinda A.; Meijer, Chris J.L.M.; Berge, Rosita L. ten; Hack, C. Erik; Muris, Jettie J.F.; Dukers, Danny F.; Chott, Andreas; Kazama, Yoshiaki; Oudejans, Joost J.; Berkum, Oskar van; Kummer, J. Alain

doi:10.1182/blood.v99.1.232

Cited by 138 publications

(127 citation statements)

References 32 publications

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“…Early studies with solid tumors and lymphomas in humans and mice suggested that overexpression of PI-9 or SPI-6 may be a mechanism by which tumors evade the GzmB/ perforin pathway (105,107). In these studies there is no comparison of serpin expression in tumor cells relative to corresponding normal tissues, thus making the results difficult to interpret.…”

Section: Gzmb Endogenous Inhibitorsmentioning

confidence: 55%

Death by a Thousand Cuts: Granzyme Pathways of Programmed Cell Death

Chowdhury

Lieberman

2008

Annu. Rev. Immunol.

555

580

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The granzymes are cell death-inducing enzymes, stored in the cytotoxic granules of cytotoxic T lymphocytes and natural killer cells, that are released during granule exocytosis when a specific virus-infected or transformed target cell is marked for elimination. Recent work suggests that this homologous family of serine esterases can activate at least three distinct pathways of cell death. This redundancy likely evolved to provide protection against pathogens and tumors with diverse strategies for evading cell death. This review discusses what is known about granzyme-mediated pathways of cell death as well as recent studies that implicate granzymes in immune regulation and extracellular proteolytic functions in inflammation.

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Section: Gzmb Endogenous Inhibitorsmentioning

confidence: 55%

Death by a Thousand Cuts: Granzyme Pathways of Programmed Cell Death

Chowdhury

Lieberman

2008

Annu. Rev. Immunol.

555

580

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“…13 However, PI9 is also highly expressed in cells that do not express granzyme B, such as dendritic cells, cells at immune privileged sites (placenta, testis, ovary and eye) and endothelial cells. 20 Tumors can express PI9 as well, for example various types of lymphomas, 31 20 indicating that PI9 expression is upregulated during the malignant transformation. Besides inhibition of GrB, our findings indicate another mechanism by which PI9 may protect tumor cells from the immune response.…”

Section: Discussionmentioning

confidence: 99%

Ectopic expression of the serine protease inhibitor PI9 modulates death receptor-mediated apoptosis

et al. 2007

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Apoptosis is a highly controlled process, whose triggering is associated with the activation of caspases. Apoptosis can be induced via a subgroup of the tumor necrosis factor (TNF) receptor superfamily, which recruit and activate pro-caspase-8 and -10. Regulation of apoptosis is achieved by several inhibitors, including c-FLICE-inhibitory protein, which prevents apoptosis by inhibiting the pro-apoptotic activation of upstream caspases. Here we show that the human intracellular serine protease inhibitor (serpin), protease inhibitor 9 (PI9), inhibits TNF-, TNF-related apoptosis-inducing ligand-and Fas ligand-mediated apoptosis in certain TNF-sensitive cell lines. The reactive center P1 residue of PI9 was required for this inhibition since PI9 harboring a GluAla mutation in its reactive center failed to impair death receptor-induced cell death. This suggests a classical serpin-protease interaction. Indeed, PI9 inhibited apoptotic death by directly interacting with the intermediate active forms of caspase-8 and -10. This indicates that PI9 can regulate pro-apoptotic apical caspases. Apoptosis is a highly controlled process, whose triggering is mainly associated with the activation of proteolytic enzymes.1,2 In the immune system, apoptotic death in target cells is mediated by cytotoxic lymphocytes (CL) including natural killer cells and cytotoxic T lymphocytes. These cells induce apoptosis via two different pathways: (a) the degranulation pathway and (b) a membrane receptor-ligand interaction involving members of the tumor necrosis family (TNF).2,3 In both pathways, activation of protease cascades plays an essential role in apoptotic death.Granules of CL contain several serine proteases called granzymes, of which granzyme B is the most important. Granzyme B possesses a unique Asp-ase activity and, upon entering the target cell, cleaves and activates pro-caspase-3 and other substrates to initiate apoptotic death. Target cell death can also be induced by members of the TNF family, such as membrane-bound Fas ligand (FasL) on the CL that interacts with its receptor Fas. Soluble-and membrane-bound TNF and TNF-related apoptosis-inducing ligand (TRAIL) also mediate death via their respective receptors, TNF receptor (TNF-R1) and TRAIL receptors (TRAIL-R1 and -R2). 4 Activation of these receptors lead to recruitment of the adaptor molecule, Fas-associated death domain (FADD). 5,6The death effector domain (DED) of FADD then recruits procaspase-8 and procaspase-10 via homotypic interaction with the DEDs in these caspases. Ligand, receptor, adaptor proteins and caspases form the death-inducing signaling complex (DISC). The high local concentration of procaspases promotes auto-activation and release into the cytosol triggering subsequent cleavage of downstream effector caspases (caspase-3, -6 and -7) leading to apoptotic death. Altogether, the induction and execution of apoptosis by CLs is mediated both by cysteine proteases, such as caspases, and by serine proteases, such as granzymes.Activation of apoptotic proteases within the...

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“…Resistance to such enzymatic activity is another potential avenue by which a tumor may evade killing usually triggered by CD20 binding. Expression of protease inhibitor 9 has now documented the existence of this resistance mechanism (Bladergroen et al, 2002). Thus, the final decision of an effector cell to kill a target or not can be affected by a complex interplay of signals, including the nature of the interaction of the antibody with FcgR that could be altered by either the antibody or the FcgR, the presence of other activating or inhibitory receptors and their ligands, or perturbation of the downstream intracellular signals.…”

Section: Antibody-dependent Cellular Cytotoxicitymentioning

confidence: 99%