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Targeting Lymphotoxin ß Receptor with Tumor-Specific T Lymphocytes for Tumor Regression

Authors' Affiliations: ¹ Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, Georgia and ² Laboratory of Tumor Immunology and Biology, National Cancer Institute, NIH, Bethesda, Maryland

Requests for reprints: Kebin Liu, Department of Biochemistry and Molecular Biology, Medical College of Georgia, 1459 Laney Walker Boulevard, Augusta, GA 30912. Phone: 706-721-9483; Fax: 706-721-6608; E-mail: Kliu{at}mcg.edu.

Purpose: 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 LTßR with tumor-specific CTLs to induce tumor rejection in vivo.

Experimental Design: 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 LTßR, a cell surface death receptor, in causing tumor rejection by CTLs was analyzed by LTßR-specific neutralizing monoclonal antibody in vitro. The specificity and efficacy of LTßR in the suppression of established tumors was further investigated by silencing LTßR 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 LTßR was expressed on the tumor cell surface, and LT, LTß, and LIGHT, all of which are ligands for LTßR, were either constitutively expressed or activated in the tumor-specific CTLs and primary CD8⁺ T cells. Blocking LTßR with LTßR-specific neutralizing monoclonal antibody decreased CTL cytotoxicity in vitro. Silencing LTßR using LTßR-specific short hairpin RNA reduced the ability of pfp CTLs to induce tumor rejection in vivo.

Conclusion: LTßR directly mediates CTL-directed tumor rejection in vivo. Targeting LTßR with tumor-specific CTLs is a potential therapeutic approach.

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