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

Author:

Bots Michael1,Kolfschoten Ingrid G. M.1,Bres Sandra A.1,Rademaker Mirjam T. G. A.1,de Roo Guido M.1,Krüse Margreet1,Franken Kees L. M. C.1,Hahne Michael1,Froelich Christopher J.1,Melief Cornelis J. M.1,Offringa Rienk1,Medema Jan Paul1

Affiliation:

1. From the Department of Clinical Oncology, Leiden University Medical Center, The Netherlands; Division of Tumor Biology, The Netherlands Cancer Institute, Amsterdam; Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, The Netherlands; Institut de Génétique Moléculaire de Montpellier, CNRS UMR5535, France; and Department of Medicine, Evanston Northwestern Healthcare Research Institute, IL.

Abstract

AbstractTumors 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.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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