Galectin-3 captures interferon-gamma in the tumor matrix reducing chemokine gradient production and T-cell tumor infiltration.

ABSTRACT: The presence of T cells in tumors predicts overall survival for cancer patients. However, why most tumors are poorly infiltrated by T cells is barely understood. T-cell recruitment towards the tumor requires a chemokine gradient of the critical IFN?-induced chemokines CXCL9/10/11. Here, we describe how tumors can abolish IFN?-induced chemokines, thereby reducing T-cell attraction. This mechanism requires extracellular galectin-3, a lectin secreted by tumors. Galectins bind the glycans of glycoproteins and form lattices by oligomerization. We demonstrate that galectin-3 binds the glycans of the extracellular matrix and those decorating IFN?. In mice bearing human tumors, galectin-3 reduces IFN? diffusion through the tumor matrix. Galectin antagonists increase intratumoral IFN? diffusion, CXCL9 gradient and tumor recruitment of adoptively transferred human CD8⁺ T cells specific for a tumor antigen. Transfer of T cells reduces tumor growth only if galectin antagonists are injected. Considering that most human cytokines are glycosylated, galectin secretion could be a general strategy for tumor immune evasion.Most tumours are poorly infiltrated by T cells. Here the authors show that galectin-3 secreted by tumours binds both glycosylated IFN? and glycoproteins of the tumour extracellular matrix, thus avoiding IFN? diffusion and the formation of an IFN?-induced chemokine gradient required for T cell infiltration.

SUBMITTER: Gordon-Alonso M 

PROVIDER: S-EPMC5630615 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature