2 research outputs found
An Orally Active Galectin-3 Antagonist Inhibits Lung Adenocarcinoma Growth and Augments Response to PD-L1 Blockade
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
Galectin-3 regulation of non small cell lung cancer growth
Galectin-3 is a β-galactoside binding lectin expressed in tumour cells
and macrophages and has been associated with increased malignancy in a
variety of cancers. Previous work has shown that galectin-3 is an
important regulator of macrophage function, promoting an alternative (M2)
phenotype which potentiates chronic inflammation and fibrosis. Tumour
associated macrophages (TAMs) adopt an M2 phenotype and are thought
to promote tumour growth by down regulating T cell effector function
and promoting angiogenesis.
This project examines the hypothesis that host galectin-3 promotes lung
cancer growth and spread. In order to test this hypothesis, Lewis Lung
Carcinoma tumour growth and metastasis was investigated in strain
matched mice either expressing or deficient in galectin-3. The Lewis
Lung Carcinoma cell line (LLC1) is a spontaneous lung carcinoma line,
derived from C57BL/6 mice, which readily forms tumours when
transplanted. Furthermore, LLC1 cells were stably transfected with a
Luciferase expressing vector in order to assist detection of tumour
growth and metastasis in vivo.
An orthotopic model of LLC1 growth suggested that galectin-3-/- animals do
not support lung carcinoma growth and spread. This finding was
confirmed by a subcutaneous model of cancer growth, where it was
found that wild type animals display a higher proportion of macrophages
expressing a prototypic M2 marker around tumour sites compared to
galectin-3-/- animals. M2-promoting cytokine transcripts were also reduced
in galectin-3-/- mice. Additionally, tumours of wild type mice were more
invasive and presented more mature blood vessels compared to galectin-3-/-
mice.
To specifically address the role of recruited cells on tumour growth,
metastasis and the inflammation profile around tumour sites, in relation
to galectin-3 expression, bone marrow cells (BMCs) were transplanted
from wild type to galectin-3-/- mice and vice versa. It was shown that
galectin-3 positive BMCs restore the wild type phenotype of tumour
growth in galectin-3-/- mice, while galectin-3 deficient BMCs impair
tumour growth in wild type animals. Furthermore, macrophage ablation
experiments demonstrated incapacity for tumour establishment in the
absence of macrophages.
A series of experiments investigating reported inhibition of galectin-3
by modified citrus pectin (MCP) via competitive inhibition did not provide
conclusive results. MCP had no effect in vivo, but was able to inhibit
LLC1 cell growth in vitro. Most importantly though, results were
inconclusive as to whether galectin-3 binds MCP. Some ligand
displacement was seen, but direct binding of the molecules could not be
shown.
In general, the results obtained demonstrate a strong pro-tumoural effect
of galectin-3 on growth, tissue invasion and metastasis of LLC1 tumours
via an increased proportion of Ym1-expressing macrophages around
tumour sites. It was shown that macrophages are key cells for tumour
initiation and that BMC phenotype in relation to galectin-3 expression
determines the phenotype of tumour development in subcutaneous and
orthotopic LLC1 models. Therefore, galectin-3 has a strong regulatory effect
on tumour phenotype and could present a key target in the management of
lung carcinomas