A galectin-3 ligand corrects the impaired function of human CD4 and CD8 tumor-infiltrating lymphocytes and favors tumor rejection in mice.
Human CD8(+) tumor-infiltrating T lymphocytes (TIL), in contrast with CD8(+) blood cells, show impaired IFN-γ secretion on ex vivo restimulation. We have attributed the impaired IFN-γ secretion to a decreased mobility of T-cell receptors on trapping in a lattice of glycoproteins clustered by extracellular galectin-3. Indeed, we have previously shown that treatment with N-acetyllactosamine, a galectin ligand, restored this secretion. We strengthened this hypothesis here by showing that CD8(+) TIL treated with an anti-galectin-3 antibody had an increased IFN-γ secretion. Moreover, we found that GCS-100, a polysaccharide in clinical development, detached galectin-3 from TIL and boosted cytotoxicity and secretion of different cytokines. Importantly, we observed that not only CD8(+) TIL but also CD4(+) TIL treated with GCS-100 secreted more IFN-γ on ex vivo restimulation. In tumor-bearing mice vaccinated with a tumor antigen, injections of GCS-100 led to tumor rejection in half of the mice, whereas all control mice died. In nonvaccinated mice, GCS-100 had no effect by itself. These results suggest that a combination of galectin-3 ligands and therapeutic vaccination may induce more tumor regressions in cancer patients than vaccination alone.
Demotte
Nathalie
N
Ludwig Institute for Cancer Research and Université Catholique de Louvain, de Duve Institute, Brussels, Belgium.
Wieërs
Grégoire
G
Van Der Smissen
Patrick
P
Moser
Muriel
M
Schmidt
Christopher
C
Thielemans
Kris
K
Squifflet
Jean-Luc
JL
Weynand
Birgit
B
Carrasco
Javier
J
Lurquin
Christophe
C
Courtoy
Pierre J
PJ
van der Bruggen
Pierre
P
D000606:Amino Sugars / Q000494:pharmacology*; D000818:Animals; D001201:Ascites / Q000276:immunology / Q000473:pathology; D001943:Breast Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology / Q000494:pharmacology; D045744:Cell Line, Tumor; D005260:Female; D037502:Galectin 3 / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D008024:Ligands; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology*; D034801:Mastocytoma / Q000188:drug therapy / Q000276:immunology; D008545:Melanoma / Q000276:immunology / Q000473:pathology / Q000628:therapy; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000628:therapy; D016066:Pleural Effusion, Malignant / Q000276:immunology / Q000473:pathology; D011134:Polysaccharides / Q000494:pharmacology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology
D000606:Amino Sugars; D019496:Cancer Vaccines; C505531:GCS-100; D037502:Galectin 3; D008024:Ligands; D011134:Polysaccharides; D011948:Receptors, Antigen, T-Cell; C000458:N-acetyllactosamine; D007371:Interferon-gamma