LIGHT, a novel ligand for lymphotoxin beta receptor and TR2/HVEM induces apoptosis and suppresses in vivo tumor formation via gene transfer.
LIGHT is a new member of tumor necrosis factor (TNF) cytokine family derived from an activated T cell cDNA library. LIGHT mRNA is highly expressed in splenocytes, activated PBL, CD8(+) tumor infiltrating lymphocytes, granulocytes, and monocytes but not in the thymus and the tumor cells examined. Introduction of LIGHT cDNA into MDA-MB-231 human breast carcinoma caused complete tumor suppression in vivo. Histological examination showed marked neutrophil infiltration and necrosis in LIGHT expressing but not in the parental or the Neo-transfected MDA-MB-231 tumors. Interferon gamma (IFNgamma) dramatically enhances LIGHT-mediated apoptosis. LIGHT protein triggers apoptosis of various tumor cells expressing both lymphotoxin beta receptor (LTbetaR) and TR2/HVEM receptors, and its cytotoxicity can be blocked specifically by addition of a LTbetaR-Fc or a TR2/HVEM-Fc fusion protein. However, LIGHT was not cytolytic to the tumor cells that express only the LTbetaR or the TR2/HVEM or hematopoietic cells examined that express only the TR2/HVEM, such as PBL, Jurkat cells, or CD8(+) TIL cells. In contrast, treatment of the activated PBL with LIGHT resulted in release of IFNgamma. Our data suggest that LIGHT triggers distinct biological responses based on the expression patterns of its receptors on the target cells. Thus, LIGHT may play a role in the immune modulation and have a potential value in cancer therapy.
Zhai
Y
Y
Human Genome Sciences, Inc., Rockville, Maryland 20850, USA.
Guo
R
R
Hsu
T L
TL
Yu
G L
GL
Ni
J
J
Kwon
B S
BS
Jiang
G W
GW
Lu
J
J
Tan
J
J
Ugustus
M
M
Carter
K
K
Rojas
L
L
Zhu
F
F
Lincoln
C
C
Endress
G
G
Xing
L
L
Wang
S
S
Oh
K O
KO
Gentz
R
R
Ruben
S
S
Lippman
M E
ME
Hsieh
S L
SL
Yang
D
D
D017209:Apoptosis; D002874:Chromosome Mapping; D016895:Culture Media, Serum-Free; D005260:Female; D018014:Gene Transfer Techniques; D016147:Genes, Tumor Suppressor; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007371:Interferon-gamma / Q000378:metabolism; D008024:Ligands; D008213:Lymphocyte Activation; D016246:Lymphocytes, Tumor-Infiltrating; D053259:Lymphotoxin beta Receptor; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D053240:Receptors, Tumor Necrosis Factor, Member 14; D011991:Receptors, Virus / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
D016895:Culture Media, Serum-Free; C505697:LTBR protein, human; D008024:Ligands; D053259:Lymphotoxin beta Receptor; D008565:Membrane Proteins; D018124:Receptors, Tumor Necrosis Factor; D053240:Receptors, Tumor Necrosis Factor, Member 14; D011991:Receptors, Virus; C506028:TNFRSF14 protein, human; C505914:TNFSF14 protein, human; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma