An orally active galectin-3 antagonist inhibits lung adenocarcinoma growth and augments response to PD-L1 blockade
(2019) In Cancer Research 79(7). p.1480-1492- Abstract
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 β-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... (More)
(Less)
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 β-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.
- author
- organization
- publishing date
- 2019
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Cancer Research
- volume
- 79
- issue
- 7
- pages
- 13 pages
- publisher
- American Association for Cancer Research Inc.
- external identifiers
-
- pmid:30674531
- scopus:85064195267
- ISSN
- 0008-5472
- DOI
- 10.1158/0008-5472.CAN-18-2244
- language
- English
- LU publication?
- yes
- id
- d23a5cfb-8cd9-4ddb-bcbc-f3ae17f3a5ba
- alternative location
- https://aacrjournals.org/cancerres/article/79/7/1480/640520/An-Orally-Active-Galectin-3-Antagonist-Inhibits
- date added to LUP
- 2019-04-26 09:47:15
- date last changed
- 2024-06-25 10:40:50
@article{d23a5cfb-8cd9-4ddb-bcbc-f3ae17f3a5ba,
abstract = {{<p><br>
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 β-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 <br>
<sup>+</sup><br>
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. <br>
</p>}},
author = {{Vuong, Lynda and Kouverianou, Eleni and Rooney, Claire M. and McHugh, Brian J. and Howie, Sarah E.M. and Gregory, Christopher D. and Forbes, Stuart J. and Henderson, Neil C. and Zetterberg, Fredrik R. and Nilsson, Ulf J. and Leffler, Hakon and Ford, Paul and Pedersen, Anders and Gravelle, Lise and Tantawi, Susan and Schambye, Hans and Sethi, Tariq and MacKinnon, Alison C.}},
issn = {{0008-5472}},
language = {{eng}},
number = {{7}},
pages = {{1480--1492}},
publisher = {{American Association for Cancer Research Inc.}},
series = {{Cancer Research}},
title = {{An orally active galectin-3 antagonist inhibits lung adenocarcinoma growth and augments response to PD-L1 blockade}},
url = {{http://dx.doi.org/10.1158/0008-5472.CAN-18-2244}},
doi = {{10.1158/0008-5472.CAN-18-2244}},
volume = {{79}},
year = {{2019}},
}