The effects of FasL on inflammation and tumor survival are dependent on its expression levels.
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.
Wada
A
A
Division of Pathology, Chiba Cancer Center Research Institute, Chiba, Japan.
Tada
Y
Y
Kawamura
K
K
Takiguchi
Y
Y
Tatsumi
K
K
Kuriyama
T
T
Takenouchi
T
T
O-Wang
J
J
Tagawa
M
M
D000818:Animals; D017209:Apoptosis; D023201:CD40 Ligand / Q000494:pharmacology; D018827:Carcinoma, Lewis Lung / Q000276:immunology / Q000473:pathology*; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D053222:Fas Ligand Protein / Q000502:physiology*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D020287:In Situ Nick-End Labeling; D007249:Inflammation / Q000473:pathology; D008546:Melanoma, Experimental / Q000276:immunology / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009504:Neutrophils / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D013601:T-Lymphocytes / Q000276:immunology*; D014162:Transfection
D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D023201:CD40 Ligand