A galectin-3 ligand corrects the impaired function of human CD4 and CD8 tumor-infiltrating lymphocytes and favors tumor rejection in mice

Demotte, Nathalie;Wieers, Grégoire;Van Der Smissen, Patrick;Moser, Muriel;van der Bruggen, Pierre;et.al.
(2010) Cancer Research — Vol. 70, n° 19, p. 7476-7488 (2010)

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Abstract
Human CD8(+) tumor-infiltrating T lymphocytes (TIL), in contrast with CD8(+) blood cells, show impaired IFN-gamma secretion upon ex vivo re-stimulation. We have attributed the impaired IFN-gamma secretion to a decreased mobility of T cell receptors upon 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 strenghtened this hypothesis here by showing that CD8(+) TIL treated with an anti-galectin-3 antibody had an increased IFN-gamma 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-gamma upon ex vivo re-stimulation. 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 non-vaccinated 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.
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Demotte, N., Wieers, G., Van Der Smissen, P., Moser, M., Schmidt, C., Thielemans, K., Squifflet, J.-L., Weynand, B., Carrasco, J., Lurquin, C., Courtoy, P., & van der Bruggen, P. (2010). A galectin-3 ligand corrects the impaired function of human CD4 and CD8 tumor-infiltrating lymphocytes and favors tumor rejection in mice. Cancer Research, 70(19), 7476-7488. https://doi.org/10.1158/0008-5472.CAN-10-0761 (Original work published 2010)