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Galectin-3 captures interferon-gamma in the tumor matrix reducing chemokine gradient production and T-cell tumor
Monica Gordon-Alonso1,2, Thibault Hirsch3, Claude Wildmann3,4
1Ludwig Institute for Cancer Research, de Duve Institute, Université catholique de Louvain, Avenue Hippocrate 74, 1200, Brussels, Belgium. monica.gordon-alonso@bru.licr.org.
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 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.
Insights
Tumors evade T cells by secreting galectin-3, which blocks immune-attracting chemokines. Blocking galectin-3 restores T cell infiltration and reduces tumor growth, offering a new cancer therapy strategy.
Area of Science:
- Immunology
- Cancer Biology
- Glycobiology
Background:
- T cell infiltration in tumors correlates with patient survival.
- The poor infiltration of tumors by T cells is a major obstacle in cancer therapy.
- T cell recruitment relies on chemokine gradients, particularly those induced by interferon-gamma (IFNγ).
Purpose of the Study:
- To elucidate the mechanism by which tumors evade T cell infiltration.
- To investigate the role of extracellular galectin-3 in tumor immune evasion.
- To explore galectin antagonists as a potential cancer immunotherapy.
Main Methods:
- Investigated galectin-3 binding to extracellular matrix and IFNγ.
- Utilized mouse models with human tumors to assess galectin-3's effect on IFNγ diffusion.
- Administered galectin antagonists to evaluate their impact on T cell recruitment and tumor growth.
Main Results:
- Tumor-secreted galectin-3 binds to glycosylated IFNγ and extracellular matrix components.
- Galectin-3 hinders IFNγ diffusion within the tumor microenvironment, disrupting chemokine gradients.
- Galectin antagonists restored IFNγ diffusion, enhanced chemokine gradients, and promoted the infiltration of CD8+ T cells, leading to reduced tumor growth.
Conclusions:
- Tumor-secreted galectin-3 is a key mechanism for immune evasion by preventing T cell infiltration.
- Targeting galectin-3 with antagonists can enhance anti-tumor immunity by facilitating T cell recruitment.
- This strategy holds promise as a general approach to overcoming tumor immune evasion, given the glycosylation of many cytokines.
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