Blockade of the granzyme B/perforin pathway through overexpression of the serine protease inhibitor PI-9/SPI-6 constitutes a mechanism for immune escape by tumors

The concept for cellular immunotherapy of solid tumors relies heavily on th e capacity of class I MHC-restricted cytotoxic T lymphocytes (CTLs) to elim inate tumor cells. However, tumors often have managed to escape from the cy tolytic machinery of these effector cells. Therefore, it is very important to chart the mechanisms through which this escape can occur. Target-cell ki lling by CTLs involves the induction of apoptosis by two major mechanisms: through death receptors and the perforin/granzyme B (GrB) pathway. Whereas tumors previously were shown to exhibit mechanisms for blocking the death r eceptor pathway, we now demonstrate that they also can resist CTL-mediated killing through interference with the perforin/GrB pathway. This escape mec hanism involves expression of the serine protease inhibitor PI-9/SPI-6, whi ch inactivates the apoptotic effector molecule GrB. Expression of PI-9 was observed in a variety of human and murine tumors. Moreover, we show that, i ndeed, expression results in the resistance of tumor cells to CTL-mediated killing both in vitro and in vivo. Our data reveal that PI-9/SPI-6 is an im portant parameter determining the success of T cell-based immunotherapeutic modalities against cancer.