Stimulation of non-Hodgkin's lymphoma via HVEM: an alternate and safe way to increase Fas-induced apoptosis and improve tumor immunogenicity.
Stimulation by CD40 ligand (L) improves B-cell malignancy immunogenicity, and also induces proliferative signals. To avoid these tumorigenic effects, we studied an alternate way of tumor-cell stimulation by homologous to lymphotoxin, inducible expression, competing for GpD of herpesvirus, which binds to the herpesvirus entry mediator (HVEM), and is expressed on T-lymphocytes (LIGHT), the ligand for HVEM, a new member of the tumor necrosis factor (TNF)/TNF-receptor (-R) family. HVEM is constitutively expressed on the surface of tumor B cells. We focused our attention on mantle cell lymphoma, a subtype of B-cell malignancy of poor prognosis. Triggering by LIGHT, in contrast to CD40L stimulation, did not increase lymphoma proliferation nor decrease chemotherapy entrance. We observed an upregulation of the TNFR apoptosis-inducing ligand Fas, and in contrast to CD40L-induced protection, an enhancement of lymphoma sensitivity to Fas-induced apoptosis. LIGHT triggering increased lymphoma cell recognition in a mixed lymphocyte response. In conclusion, LIGHT-mediated triggering renders B-cell lymphomas more immunogenic and sensitive to apoptosis, without inducing proliferation. Since LIGHT triggering also enhances the functions of T-lymphocytes and dendritic cells, it could be a unique way to restore an efficient cancer control by its pleiotropic effects on immune effectors and tumor cells.
Costello
R T
RT
Centre Lutte Contre Cancer, Marseille, France.
Mallet
F
F
Barbarat
B
B
Schiano De Colella
J-M
JM
Sainty
D
D
Sweet
R W
RW
Truneh
A
A
Olive
D
D
D017209:Apoptosis / Q000235:genetics* / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D019013:CD40 Antigens / Q000378:metabolism; D002448:Cell Adhesion / Q000276:immunology; D016923:Cell Death / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D007167:Immunotherapy; D007376:Interleukin-2 / Q000378:metabolism; D008024:Ligands; D007959:Lymphocyte Culture Test, Mixed; D020522:Lymphoma, Mantle-Cell / Q000276:immunology / Q000628:therapy; D008228:Lymphoma, Non-Hodgkin / Q000276:immunology* / Q000628:therapy*; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics*; D053240:Receptors, Tumor Necrosis Factor, Member 14; D011991:Receptors, Virus / Q000235:genetics*; D014162:Transfection; D019014:fas Receptor / Q000378:metabolism*
D019013:CD40 Antigens; D007376:Interleukin-2; D008024:Ligands; D018124:Receptors, Tumor Necrosis Factor; D053240:Receptors, Tumor Necrosis Factor, Member 14; D011991:Receptors, Virus; C506028:TNFRSF14 protein, human; D019014:fas Receptor