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


METHODS
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.


RESULTS
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.


CONCLUSIONS
LTbetaR directly mediates CTL-directed tumor rejection in vivo. Targeting LTbetaR with tumor-specific CTLs is a potential therapeutic approach.
Yang
Dafeng
D
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, Georgia 30912, USA.
Ud Din
Najam
N
Browning
Darren D
DD
Abrams
Scott I
SI
Liu
Kebin
K
D000818:Animals; D003602:Cytotoxicity, Immunologic; D005260:Female; D006084:Graft Rejection; D016219:Immunotherapy, Adoptive; D007371:Interferon-gamma / Q000494:pharmacology; D053259:Lymphotoxin beta Receptor / Q000032:analysis / Q000502:physiology; D053308:Lymphotoxin-beta / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000628:therapy*; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins / Q000502:physiology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14 / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019014:fas Receptor / Q000502:physiology