Galectin-3 targeted therapy for lung adenocarcinoma
Lynda Vuong1, Fredrik Zetterberg2, Hakon Leffler2, Ulf J Nilsson2, Lise Gavelle2, Sue Tantawi2, Anders Pedersen2, Hans Schambye2, Alison Mackinnon3 1Department of Respiratory Medicine and Allergy, Kings College London UK; 2Galecto Biotech AB - Copenhagen, Denmark;3MRC Centre for Inflammation Research at University of Edinburgh UK Galectin-3 is a β-galactoside-binding lectin highly expressed within the tumor microenvironment by tumor cells, tumor-associated macrophages (TAMs) and activated T cells. Galectin-3 expression correlates with a poor prognosis for non-small cell lung cancer patients, however, the mechanisms whereby galectin-3 may support tumour growth and spread is not completely known. In this study we demonstrate that galectin-3-/- mice do not support syngeneic Lewis Lung carcinoma (LLC1) tumor growth and metastatic spread in orthotopic and subcutaneous models of lung adenocarcinoma (96.9% smaller tumours compared to wildtype animals, p<0.0001). Using in vivo macrophage ablation and generation of bone marrow chimeric mice, our data suggests that galectin-3 expressing bone marrow derived macrophages are key drivers of tumor progression. We show that galectin-3 targeted therapy with a novel orally active, small molecule galectin-3 antagonist reduced lung adenocarcinoma growth and metastasis in syngeneic LLC1 and human A549 xenograft models. Furthermore we showed that pharmacological inhibition of galectin-3 enhanced infiltration and activation of tumour infiltrating CD8 and CD4 T cells and promoted tumor cell apoptosis. This effect was further enhanced by combination treatment with an immune checkpoint inhibitory antibody targeting programmed death-ligand 1 (PD-L1). Thus these galectin-3 inhibitors could provide a novel non-toxic treatment for lung adenocarcinoma and boost immune-infiltration and corresponding responses to current immune checkpoint therapies.
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