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An Orally Active Galectin-3 Antagonist Inhibits Lung Adenocarcinoma Growth and Augments Response to PD-L1 Blockade.
Vuong, Lynda; Kouverianou, Eleni; Rooney, Claire M; McHugh, Brian J; Howie, Sarah E M; Gregory, Christopher D; Forbes, Stuart J; Henderson, Neil C; Zetterberg, Fredrik R; Nilsson, Ulf J; Leffler, Hakon; Ford, Paul; Pedersen, Anders; Gravelle, Lise; Tantawi, Susan; Schambye, Hans; Sethi, Tariq; MacKinnon, Alison C.
Afiliación
  • Vuong L; Department of Asthma, Allergy and Respiratory Science, King's College London, Guy's Hospital, London, United Kingdom.
  • Kouverianou E; Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh Bioquarter, Edinburgh, United Kingdom.
  • Rooney CM; Department of Asthma, Allergy and Respiratory Science, King's College London, Guy's Hospital, London, United Kingdom.
  • McHugh BJ; Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh Bioquarter, Edinburgh, United Kingdom.
  • Howie SEM; Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh Bioquarter, Edinburgh, United Kingdom.
  • Gregory CD; Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh Bioquarter, Edinburgh, United Kingdom.
  • Forbes SJ; MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh Bioquarter, Edinburgh, United Kingdom.
  • Henderson NC; Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh Bioquarter, Edinburgh, United Kingdom.
  • Zetterberg FR; Galecto Biotech, Copenhagen, Denmark.
  • Nilsson UJ; Department of Chemistry, Centre for Analysis and Synthesis, Lund University, Lund, Sweden.
  • Leffler H; Department of Laboratory Medicine, Section MIG, Lund University, Lund, Sweden.
  • Ford P; Galecto Biotech, Copenhagen, Denmark.
  • Pedersen A; Galecto Biotech, Copenhagen, Denmark.
  • Gravelle L; Galecto Biotech, Copenhagen, Denmark.
  • Tantawi S; Galecto Biotech, Copenhagen, Denmark.
  • Schambye H; Galecto Biotech, Copenhagen, Denmark.
  • Sethi T; Department of Asthma, Allergy and Respiratory Science, King's College London, Guy's Hospital, London, United Kingdom.
  • MacKinnon AC; Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh Bioquarter, Edinburgh, United Kingdom. a.mackinnon@ed.ac.uk.
Cancer Res ; 79(7): 1480-1492, 2019 04 01.
Article en En | MEDLINE | ID: mdl-30674531
A combination therapy approach is required to improve tumor immune infiltration and patient response to immune checkpoint inhibitors that target negative regulatory receptors. Galectin-3 is a ß-galactoside-binding lectin that is highly expressed within the tumor microenvironment of aggressive cancers and whose expression correlates with poor survival particularly in patients with non-small cell lung cancer (NSCLC). To examine the role of galectin-3 inhibition in NSCLC, we tested the effects of galectin-3 depletion using genetic and pharmacologic approaches on syngeneic mouse lung adenocarcinoma and human lung adenocarcinoma xenografts. Galectin-3-/- mice developed significantly smaller and fewer tumors and metastases than syngeneic C57/Bl6 wild-type mice. Macrophage ablation retarded tumor growth, whereas reconstitution with galectin-3-positive bone marrow restored tumor growth in galectin-3-/- mice, indicating that macrophages were a major driver of the antitumor response. Oral administration of a novel small molecule galectin-3 inhibitor GB1107 reduced human and mouse lung adenocarcinoma growth and blocked metastasis in the syngeneic model. Treatment with GB1107 increased tumor M1 macrophage polarization and CD8+ T-cell infiltration. Moreover, GB1107 potentiated the effects of a PD-L1 immune checkpoint inhibitor to increase expression of cytotoxic (IFNγ, granzyme B, perforin-1, Fas ligand) and apoptotic (cleaved caspase-3) effector molecules. In summary, galectin-3 is an important regulator of lung adenocarcinoma progression. The novel galectin-3 inhibitor presented could provide an effective, nontoxic monotherapy or be used in combination with immune checkpoint inhibitors to boost immune infiltration and responses in lung adenocarcinoma and potentially other aggressive cancers. SIGNIFICANCE: A novel and orally active galectin-3 antagonist inhibits lung adenocarcinoma growth and metastasis and augments response to PD-L1 blockade.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/7/1480/F1.large.jpg.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Galectina 3 / Proliferación Celular / Antígeno B7-H1 / Adenocarcinoma del Pulmón / Neoplasias Pulmonares Límite: Animals / Female / Humans Idioma: En Revista: Cancer Res Año: 2019 Tipo del documento: Article País de afiliación: Reino Unido

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Galectina 3 / Proliferación Celular / Antígeno B7-H1 / Adenocarcinoma del Pulmón / Neoplasias Pulmonares Límite: Animals / Female / Humans Idioma: En Revista: Cancer Res Año: 2019 Tipo del documento: Article País de afiliación: Reino Unido