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

Monica Gordon-Alonso,Thibault Hirsch,Pierre Van Der Bruggen,Claude Wildmann

doi:10.1038/s41467-017-00925-6

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.

Highlights

The presence of T cells in tumors predicts overall survival for cancer patients
As galectins bind glycosylated moieties that decorate glycoproteins, we examined whether galectin-3 interacts with glycosylated human cytokines and chemokines
Magnetic beads coated with recombinant human galectin-3 were immersed for 1 h in a solution of human recombinant N-glycosylated IFNγ produced by hamster cells

Summary

Introduction

The presence of T cells in tumors predicts overall survival for cancer patients. why most tumors are poorly infiltrated by T cells is barely understood. 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. Galectin antagonists increase intratumoral IFNγ diffusion, CXCL9 gradient and tumor recruitment of adoptively transferred human CD8+ T cells specific for a tumor antigen. CXCL9 and CXCL10 stand out as their tumor expression correlates with prolonged disease-free survival of patients with colorectal carcinoma and other cancers[9] These chemokines attract activated T cells into the tumor and prevent tumor angiogenesis[10]. Proteins and lipids with abnormal glycosylation may form new interactions with lectins, i.e., proteins that bind glycans These interactions have been reported to promote metastasis and immune evasion[21]. The combination of these multiple interactions results in strong binding and has an enormous impact in many biological processes[23]

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