Improving the clinical efficacy of cancer vaccines by targeting immune suppression in human tumors

The identification of tumor-specific antigens recognized by T lymphocytes on human cancer cells has elicited numerous vaccination trials of cancer patients with defined tumor antigens. These treatments have induced T cell responses but have shown a low clinical efficacy in tumor-bearing melanoma patients. Immunosuppression at the tumor sites is the most likely explanation for the poor effectiveness of cancer vaccines. Many researchers are trying to decipher the underlying immunosuppressive mechanism. Galectin-3, a lectin secreted by tumor cells and macrophages, plays a role in the dysfunction of tumor-infiltrating T lymphocytes (TIL). We have observed that human TIL, in contrast with CD8 blood cells, show impaired IFN-γ secretion and cytotoxicity. TIL dysfunction correlates with the segregation of T cell receptor (TCR) and CD8 co-receptor at the T cell surface. Treating TIL with soluble galectin ligands or an anti-galectin-3 antibody restored IFN-γ secretion, cytotoxicity and TCR/CD8 co-localization. Our working hypothesis is that TIL, having been stimulated recently by their antigen, harbor a set of glycans that contain numerous ligands for galectins, which block their proper function. In agreement with this hypothesis, we have recently observed that, compared to resting CD8 T cell clones, the N-glycans of recently activated clones contains more multi-antennary N-glycans and consists of longer LacNAc chains. We propose that therapeutic vaccines combined with soluble galectin ligands could reverse local immunosuppression at the tumor site and may induce more tumor regressions in cancer patients than vaccination alone.