Abstract
Several galectins are released by tumor cells and macrophages and accumulate in the tumor microenvironment. Galectin-1 and -3 were found to bind to glycosylated receptors at the surface of tumor-infiltrating lymphocytes (TIL), forming glycoprotein-galectin lattices that could reduce the motility and therefore the functionality of surface molecules. In contrast to blood T cells, human TIL show defective IFN-γ secretion upon ex vivo stimulation. We have previously shown that extracellular galectin-3 participates in the impairment of TIL functions. Indeed, disruption of glycoprotein-galectin-3 lattices using anti-galectin-3 antibodies, or N-acetyllactosamine as a competing sugar, boosted cytokine secretion by TIL. Here we have tested a clinical grade galectin antagonist: GM-CT-01, a galactomannan obtained from guar gum reported to be safe in more than 50 patients with cancer. TIL were isolated from human tumor ascites, treated for 2 to 20 hours with galectin antagonists and tested for function. We found that GM-CT-01 boosts cytotoxicity of CD8(+) TIL and their IFN-γ secretion in a dose-dependent manner. Treating TIL obtained from patients with various cancers, during a few hours, resulted in an increased IFN-γ secretion in up to 80% of the samples. These observations pave the way for investigating the potential benefit of this galectin antagonist in patients with cancer, alone or combined with cancer vaccination, in order to correct in vivo impaired functions of TIL.
Highlights
Accumulation of human tumor–infiltrating lymphocytes (TIL) is considered as a good prognostic factor
We found that GM-CT-01 boosts cytotoxicity of CD8þ tumorinfiltrating lymphocytes (TIL) and their IFN-g secretion in a dosedependent manner
These observations pave the way for investigating the potential benefit of this galectin antagonist in patients with cancer, alone or combined with cancer vaccination, in order to correct in vivo impaired functions of TIL
Summary
Accumulation of human tumor–infiltrating lymphocytes (TIL) is considered as a good prognostic factor (reviewed in Wie€ers; ref. 1). Accumulation of human tumor–infiltrating lymphocytes (TIL) is considered as a good prognostic factor When gene expression was analyzed in tumor samples of patients from 3 active immunization clinical trials, a gene signature, including T-cell. Authors' Affiliations: 1Ludwig Institute for Cancer Research Brussels and WELBIO; 2de Duve Institute; Departments of 3Gynecology and 4Oncology, Cliniques Universitaires Saint-Luc, Universite catholique de Louvain; 5Laboratory of Molecular and Cellular Therapy, Department of ImmunologyPhysiology, Medical School of the Vrije Universiteit Brussel, Brussels; and 6Department of Oncology, Grand Ho^pital de Charleroi, Charleroi, Belgium. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). Wiee€rs: Department of Internal Medicine, Cliniques universitaires Saint-Luc, Universite catholique de Louvain, 10 av.
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