Blood diffusion and Th1-suppressive effects of galectin-9-containing exosomes released by Epstein-Barr virus-infected nasopharyngeal carcinoma cells.
Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC) is the third most frequent virus-associated human malignancy. How this tumor escapes immune recognition despite the expression of several viral antigens has remained poorly understood. Our previous in vitro studies have shown that NPC cells release exosomes containing high amounts of galectin-9, a ligand of the membrane receptor Tim-3, which is able to induce apoptosis in mature Th1 lymphocytes. Here, we sought to determine whether galectin-9-carrying exosomes were produced in NPC patients and whether such exosomes might play a role in the immune evasion of NPC cells. We report that galectin-9-containing exosomes are selectively detected in plasma samples from NPC patients and mice xenografted with NPC tumors. The incorporation into exosomes protects galectin-9 against proteolytic cleavage but retains its Tim-3-binding capacity. Importantly, NPC exosomes induce massive apoptosis in EBV-specific CD4(+) cells used as a model of target T cells. This effect is inhibited by both anti-Tim-3 and antigalectin-9 blocking antibodies. These results indicate that blocking galectin-9/Tim-3 interaction in vivo might alleviate the Th1-suppressive effect of NPC exosomes and sustain antitumoral T-cell responses and thereby improve clinical efficacy of immunotherapeutic approaches against NPC.
Klibi
Jihène
J
Université Paris-Sud, Centre National de la Recherche Scientifique-Unité Mixte de Recherche 8126, Paris, France.
Niki
Toshiro
T
Riedel
Alexander
A
Pioche-Durieu
Catherine
C
Souquere
Sylvie
S
Rubinstein
Eric
E
Le Moulec
Sylvestre
S
Moulec
Sylvestre L E
SL
Guigay
Joël
J
Hirashima
Mitsuomi
M
Guemira
Fethi
F
Adhikary
Dinesh
D
Mautner
Josef
J
Busson
Pierre
P
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D001808:Blood Vessels / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002277:Carcinoma / Q000097:blood / Q000150:complications / Q000276:immunology* / Q000378:metabolism; D045744:Cell Line, Tumor; D004058:Diffusion; D020031:Epstein-Barr Virus Infections / Q000097:blood / Q000150:complications / Q000276:immunology* / Q000378:metabolism; D055354:Exosomes / Q000378:metabolism* / Q000473:pathology; D037161:Galectins / Q000037:antagonists & inhibitors / Q000097:blood / Q000276:immunology / Q000378:metabolism*; D006367:HeLa Cells; D000072597:Hepatitis A Virus Cellular Receptor 2; D006801:Humans; D051379:Mice; D009303:Nasopharyngeal Neoplasms / Q000097:blood / Q000150:complications / Q000276:immunology* / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D011991:Receptors, Virus / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000473:pathology; D014183:Transplantation, Heterologous; D019139:Tumor Escape / Q000276:immunology
D000906:Antibodies; D037161:Galectins; C442241:Havcr2 protein, mouse; D000072597:Hepatitis A Virus Cellular Receptor 2; C105032:LGALS9 protein, human; D011991:Receptors, Virus