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 IFNγ-induced chemokines CXCL9/10/11.,Here, we describe how tumors can abolish IFNγ-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 IFNγ.,In mice bearing human tumors, galectin-3 reduces IFNγ diffusion through the tumor matrix.,Galectin antagonists increase intratumoral IFNγ 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 IFNγ and glycoproteins of the tumour extracellular matrix, thus avoiding IFNγ diffusion and the formation of an IFNγ-induced chemokine gradient required for T cell infiltration.
Melanoma is the most fatal skin cancer displaying a high degree of molecular heterogeneity.,Phenotype switching is a mechanism that contributes to melanoma heterogeneity by altering transcription profiles for the transition between states of proliferation/differentiation and invasion/stemness.,As phenotype switching is reversible, epigenetic mechanisms, like DNA methylation, could contribute to the changes in gene expression.,Integrative analysis of methylation and gene expression datasets of five proliferative and five invasion melanoma cell cultures reveal two distinct clusters.,SOX9 is methylated and lowly expressed in the highly proliferative group.,SOX9 overexpression results in decreased proliferation but increased invasion in vitro.,In a B16 mouse model, sox9 overexpression increases the number of lung metastases.,Transcriptional analysis of SOX9-overexpressing melanoma cells reveals enrichment in epithelial to mesenchymal transition (EMT) pathways.,Survival analysis of The Cancer Genome Atlas melanoma dataset shows that metastatic patients with high expression levels of SOX9 have significantly worse survival rates.,Additional survival analysis on the targets of SOX9 reveals that most SOX9 downregulated genes have survival benefit for metastatic patients.,Our genome-wide DNA methylation and gene expression study of 10 early passage melanoma cell cultures reveals two phenotypically distinct groups.,One of the genes regulated by DNA methylation between the two groups is SOX9.,SOX9 induces melanoma cell invasion and metastasis and decreases patient survival.,A number of genes downregulated by SOX9 have a negative impact on patient survival.,In conclusion, SOX9 is an important gene involved in melanoma invasion and negatively impacts melanoma patient survival.,The online version of this article (doi:10.1186/s13059-015-0594-4) contains supplementary material, which is available to authorized users.