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A Novel, Orally Active Galectin-3 Antagonist Inhibits Lung Adenocarcinoma Growth and Augments Response to PD-L1 Blockade

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Original languageEnglish
JournalCancer Research
Early online date23 Jan 2019
DOIs
Publication statusE-pub ahead of print - 23 Jan 2019

Abstract

A combination therapy approach is required to improve tumor immune infiltration and patient response to immune checkpoint inhibitors targeting negative regulatory receptors. Galectin-3 is a β-galactoside-binding lectin highly expressed within the tumor microenvironment of high fatality cancers and its expression correlates particularly with poor survival in non-small cell lung cancer (NSCLC) patients. To examine the role of galectin-3 inhibition in NSCLC we tested the effects of galectin-3 depletion using genetic and pharmacological approaches on syngeneic mouse lung adenocarcinoma and human lung adenocarcinoma xenografts. We show that galectin-3-/- mice develop significantly smaller and fewer tumors and metastases than syngeneic C57/Bl6 wild type mice. We demonstrate that macrophages are a major driver of this response as macrophage ablation retards tumor growth whilst reconstitution with galectin-3 positive bone marrow restores tumor growth in galectin-3-/- mice. Oral administration of a novel small molecule galectin-3 inhibitor GB1107 reduces human and mouse lung adenocarcinoma growth and blocks metastasis in the syngeneic model. Treatment with GB1107 increases tumor M1 macrophage polarization and CD8+ cell infiltration. Moreover, it potentiates the effects of a PD-L1 immune checkpoint inhibitor, to increase expression of cytotoxic (IFN-, granzyme B, perforin-1, fas ligand) and apoptotic (cleaved caspase-3) effector molecules. Galectin-3 is an important regulator of lung adenocarcinoma progression. A novel galctin-3 inhibitor could provide effective non-toxic monotherapy treatment as well as in combination, boost immune-infiltration and responses to current immune checkpoint inhibitors in lung adenocarcinoma and potentially other high fatality cancers.



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