LTbR Mediates Cell Contact-Dependent CTL-Directed Anti-Tumor Cytotoxicity (50.11)

Abstract

Abstract Cytotoxic T lymphocytes (CTLs) are thought to use two cell contact-dependent effector mechanisms, perforin- and Fas-mediated cytotoxicity, to suppress tumor growth. Using a CTL adoptive immunotherapy model, we report here that perforin-deficient CTLs (pfp CTLs) exhibited a significant cytotoxicity against Fas-resistant tumors in vivo. We further demonstrated that the anti-tumor activity is directly mediated by the adoptively transferred CTLs. but does not involve CTL-secreted soluble molecules, such as IFNγ and TNFα as lytic agents, since these cytokines exhibited no direct cytotoxicity against these targets. Moreover, it was observed that LTβR, a cell-surface death receptor, is expressed on the tumor cell surface, and LTα, LTβ, and LIGHT, all of which are ligands for LTβR, were either constitutively expressed by or activated in the tumor-specific CTLs and primary CD8+ T cells. Silencing LTβR in these Fas-resistant tumor cells with LTβR-specific shRNA significantly decreased the ability of pfp CTL to mediate tumor rejection in vivo. Taken together, our data suggest that tumor-specific CTL use LTβR-mediated cytotoxicity as a third cell contact-dependent effector mechanism against tumor growth in vivo.