A role for HVEM, but not lymphotoxin-beta receptor, in LIGHT-induced tumor cell death and chemokine production.
The TNF member LIGHT also known as TL4 or TNFSF14) can play a major role in cancer control via its two receptors; it induces tumor cell death through lymphotoxin-beta receptor (LT-betaR) and ligation to the herpes virus entry mediator (HVEM) amplifies the immune response. By studying the effect of LIGHT in the transcriptional profile of a lymphoid malignancy, we found that HVEM, but not LT-betaR, stimulation induces a significant increase in the expression of chemokine genes such as IL-8, and an unexpected upregulation of apoptotic genes. This had functional consequences, since LIGHT, or HVEM mAb, thus far known to costimulate T- and B-cell activation, induced chronic lymphocytic leukemia cell death. Many of the mediators involved were identified here, with an apoptotic pathway as demonstrated by caspases activation, decrease in mitochondrial membrane potential, upregulation of the pro-apoptotic protein Bax, but also a role of TRAIL. Moreover, HVEM induced endogenous TNF-alpha production and TNF-alpha enhanced HVEM-mediated cell death. HVEM function was mainly dependent on LIGHT, since other ligands like HSV-glycoprotein D and B and T lymphocyte attenuator were essentially ineffective. In conclusion, we describe a novel, as yet unknown killing effect of LIGHT through HVEM on a lymphoid malignancy, and combined with induction of chemokine release this may represent an additional tool to boost cancer immunotherapy.
Pasero
Christine
C
INSERM UMR891, Centre de Recherche en Cancérologie de Marseille, Université de Méditerranée, Institut de Cancérologie et d'Immunologie de Marseille, Marseille, France.
Barbarat
Bernadette
B
Just-Landi
Sylvaine
S
Bernard
Alain
A
Aurran-Schleinitz
Thérèse
T
Rey
Jérome
J
Eldering
Eric
E
Truneh
Alemsedeg
A
Costello
Régis T
RT
Olive
Daniel
D
D000328:Adult; D000368:Aged; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism; D005260:Female; D019337:Hematologic Neoplasms / Q000276:immunology*; D006801:Humans; D053259:Lymphotoxin beta Receptor / Q000276:immunology / Q000378:metabolism; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000276:immunology; D008875:Middle Aged; D053240:Receptors, Tumor Necrosis Factor, Member 14 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; D016207:Cytokines; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D053259:Lymphotoxin beta Receptor; D053240:Receptors, Tumor Necrosis Factor, Member 14; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C505914:TNFSF14 protein, human; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14