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

ABSTRACT Tumors have several mechanisms to escape from the immune system. One of these involves expression of intracellular anti-cytotoxic proteins that modulate the execution of cell death. Previously, we have shown that the serpin SPI-6, which inactivates the cytotoxic protease granzyme B (GrB), is capable of preventing cytotoxic T lymphocyte (CTL)-mediated apoptosis. Despite its potent anti-apoptotic 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. 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 irreversible 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. From bloodjournal.hematologylibrary.org by guest on June 1, 2013. For personal use only.