1. ¹Division of Pathology, Chiba Cancer Center Research Institute, Chiba, Japan
2. ²Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, Japan
3. ³Division of Surgical Pathology, Chiba Cancer Center, Chiba, Japan
4. ⁴Laboratory for Antigen Receptor Diversity, Research Center for Allergy and Immunology, RIKEN Yokohama Institute, Kanagawa, Japan

Correspondence: Dr M Tagawa, Division of Pathology, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuo-ku, Chiba 260-8717, Japan. E-mail: mtagawa@chiba-cc.jp

⁵The first two authors contributed equally to this study.

Received 15 March 2006; Revised 3 July 2006; Accepted 28 August 2006; Published online 20 October 2006.

Abstract

The apoptosis-inducing Fas ligand (FasL) is expressed in a variety of human cancers and has been implicated in tumor immune evasion. Paradoxically, ectopic expression of FasL in experimental tumors triggers a neutrophil-mediated inflammatory response and tumor rejection. To resolve these conflicting findings, we have established B16 melanoma and P29 Lewis lung carcinoma lines expressing different levels of FasL and examined their tumorigenicity in vivo. While tumors with a high level of FasL were rapidly rejected as previously reported, those expressing a low level of FasL were not rejected but grew faster than did FasL-negative parental cells. The growth enhancement of FasL^low tumors was not observed in T-cell-deficient nude mice, suggesting that FasL expressed in tumors at low levels counteracted against T-cell-dependent antitumor responses. In support of this notion, FasL^low tumors were found to grow faster than parental cells in mice that had acquired tumor-specific immunity. Furthermore, histological examinations revealed apoptosis of lymphocytes in tissue sections of FasL^low tumors. These results collectively suggest that FasL on tumors is a double-edged sword: at high levels it triggers tumor rejection whereas at low levels it facilitates tumor growth possibly by suppressing antitumor immune responses.