Targeting lymphotoxin beta receptor with tumor-specific T lymphocytes for tumor regression.

Abstract

One of the impediments of immunotherapy against cancer is the suppression of tumor-specific CTLs in the tumor microenvironment, partly due to the selective inhibition of the perforin pathway and the emergence of Fas-resistant tumors. Therefore, we sought to identify perforin- and Fas-independent cytotoxic pathways and explored the potential of targeting LTbetaR with tumor-specific CTLs to induce tumor rejection in vivo. Fas-resistant tumors were examined for their susceptibility to perforin-deficient (pfp) CTLs via CTL adoptive transfer in mouse models of experimental lung metastasis. The specificity of LTbetaR, a cell surface death receptor, in causing tumor rejection by CTLs was analyzed by LTbetaR-specific neutralizing monoclonal antibody in vitro. The specificity and efficacy of LTbetaR in the suppression of established tumors was further investigated by silencing LTbetaR in tumor cells in vivo. pfp CTLs exhibited significant cytotoxicity against Fas-resistant tumors in vivo. The perforin- and Fas-independent cytotoxicity was directly mediated, at least in part, by the adoptively transferred CTLs. It was observed that LTbetaR was expressed on the tumor cell surface, and LTalpha, LTbeta, and LIGHT, all of which are ligands for LTbetaR, were either constitutively expressed or activated in the tumor-specific CTLs and primary CD8(+) T cells. Blocking LTbetaR with LTbetaR-specific neutralizing monoclonal antibody decreased CTL cytotoxicity in vitro. Silencing LTbetaR using LTbetaR-specific short hairpin RNA reduced the ability of pfp CTLs to induce tumor rejection in vivo. LTbetaR directly mediates CTL-directed tumor rejection in vivo. Targeting LTbetaR with tumor-specific CTLs is a potential therapeutic approach.