SPI-CI and SPI-6 cooperate in the protection from effector cell-mediated cytotoxicity.

Abstract:

:Tumors have several mechanisms to escape from the immune system. One of these involves expression of intracellular anticytotoxic proteins that modulate the execution of cell death. Previously, we have shown that the serine protease inhibitor (serpin) SPI-6, which inactivates the cytotoxic protease granzyme B (GrB), is capable of preventing cytotoxic T lymphocyte (CTL)-mediated apoptosis. Despite its potent antiapoptotic activity, SPI-6 does not prevent membranolysis induced by cytotoxic lymphocytes. We now provide evidence that several colon carcinoma cell lines do resist membranolysis and that this protection is dependent on SPI-6 but also requires expression of a closely related serpin called SPI-CI (serine protease inhibitor involved in cytotoxicity inhibition). Expression of SPI-CI is absent from normal colon but observed in placenta, testis, early during embryogenesis, and in cytotoxic lymphocytes. SPI-CI encodes a chymotrypsin-specific inhibitor and irreversibly interacts with purified granzyme M. Moreover, SPI-CI can protect cells from purified perforin/GrM-induced lysis. Our data therefore indicate that SPI-CI is a novel immune escape molecule that acts in concert with SPI-6 to prevent cytotoxic lymphocyte-mediated killing of tumor cells.

journal_name

Blood

journal_title

Blood

authors

Bots M,Kolfschoten IG,Bres SA,Rademaker MT,de Roo GM,Krüse M,Franken KL,Hahne M,Froelich CJ,Melief CJ,Offringa R,Medema JP

doi

10.1182/blood-2004-03-0791

subject

Has Abstract

pub_date

2005-02-01 00:00:00

pages

1153-61

issue

3

eissn

0006-4971

issn

1528-0020

pii

2004-03-0791

journal_volume

105

pub_type

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