Resistance to anti-PD-1/anti-PD-L1 : galectin-3 inhibition with GB1211 reverses galectin-3-induced blockade of pembrolizumab and atezolizumab binding to PD-1/PD-L1
(2023) In Frontiers in Immunology 14.- Abstract
BACKGROUND: Galectin-3 (Gal-3) is a β-galactoside-binding lectin that is highly expressed within the tumor microenvironment of aggressive cancers and has been suggested to predict a poor response to immune checkpoint therapy with the anti-PD-1 monoclonal antibody pembrolizumab. We aimed to assess if the effect of Gal-3 was a result of direct interaction with the immune checkpoint receptor.
METHODS: The ability of Gal-3 to interact with the PD-1/PD-L1 complex in the absence and presence of blocking antibodies was assessed in in vitro biochemical and cellular assays as well as in an in vivo syngeneic mouse cancer model.
RESULTS: Gal-3 reduced the binding of the checkpoint inhibitors pembrolizumab (anti-PD-1) and... (More)
BACKGROUND: Galectin-3 (Gal-3) is a β-galactoside-binding lectin that is highly expressed within the tumor microenvironment of aggressive cancers and has been suggested to predict a poor response to immune checkpoint therapy with the anti-PD-1 monoclonal antibody pembrolizumab. We aimed to assess if the effect of Gal-3 was a result of direct interaction with the immune checkpoint receptor.
METHODS: The ability of Gal-3 to interact with the PD-1/PD-L1 complex in the absence and presence of blocking antibodies was assessed in in vitro biochemical and cellular assays as well as in an in vivo syngeneic mouse cancer model.
RESULTS: Gal-3 reduced the binding of the checkpoint inhibitors pembrolizumab (anti-PD-1) and atezolizumab (anti-PD-L1), by potentiating the interaction between the PD-1/PD-L1 complex. In the presence of a highly selective Gal-3 small molecule inhibitor (GB1211) the binding of the anti-PD-1/anti-PD-L1 therapeutics was restored to control levels. This was observed in both a surface plasmon resonance assay measuring protein-protein interactions and via flow cytometry. Combination therapy with GB1211 and an anti-PD-L1 blocking antibody reduced tumor growth in an in vivo syngeneic model and increased the percentage of tumor infiltrating T lymphocytes.
CONCLUSION: Our study suggests that Gal-3 can potentiate the PD-1/PD-L1 immune axis and potentially contribute to the immunosuppressive signalling mechanisms within the tumor microenvironment. In addition, Gal-3 prevents atezolizumab and pembrolizumab target engagement with their respective immune checkpoint receptors. Reversal of this effect with the clinical candidate GB1211 offers a potential enhancing combination therapeutic with anti-PD-1 and -PD-L1 blocking antibodies.
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- author
- Mabbitt, Joseph ; Holyer, Ian D ; Roper, James A ; Nilsson, Ulf J LU ; Zetterberg, Fredrik R ; Vuong, Lynda ; Mackinnon, Alison C ; Pedersen, Anders and Slack, Robert J
- organization
- publishing date
- 2023
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Animals, Mice, Galectin 3, Antibodies, Blocking, Antibodies, Monoclonal, Humanized/pharmacology
- in
- Frontiers in Immunology
- volume
- 14
- article number
- 1250559
- publisher
- Frontiers Media S. A.
- external identifiers
-
- scopus:85170563796
- pmid:37701441
- ISSN
- 1664-3224
- DOI
- 10.3389/fimmu.2023.1250559
- language
- English
- LU publication?
- yes
- id
- d1815052-e4a7-4dc3-9800-7e4184b6b6db
- date added to LUP
- 2023-09-28 08:45:04
- date last changed
- 2024-04-19 01:45:44
@article{d1815052-e4a7-4dc3-9800-7e4184b6b6db,
abstract = {{<p>BACKGROUND: Galectin-3 (Gal-3) is a β-galactoside-binding lectin that is highly expressed within the tumor microenvironment of aggressive cancers and has been suggested to predict a poor response to immune checkpoint therapy with the anti-PD-1 monoclonal antibody pembrolizumab. We aimed to assess if the effect of Gal-3 was a result of direct interaction with the immune checkpoint receptor.</p><p>METHODS: The ability of Gal-3 to interact with the PD-1/PD-L1 complex in the absence and presence of blocking antibodies was assessed in in vitro biochemical and cellular assays as well as in an in vivo syngeneic mouse cancer model. </p><p>RESULTS: Gal-3 reduced the binding of the checkpoint inhibitors pembrolizumab (anti-PD-1) and atezolizumab (anti-PD-L1), by potentiating the interaction between the PD-1/PD-L1 complex. In the presence of a highly selective Gal-3 small molecule inhibitor (GB1211) the binding of the anti-PD-1/anti-PD-L1 therapeutics was restored to control levels. This was observed in both a surface plasmon resonance assay measuring protein-protein interactions and via flow cytometry. Combination therapy with GB1211 and an anti-PD-L1 blocking antibody reduced tumor growth in an in vivo syngeneic model and increased the percentage of tumor infiltrating T lymphocytes. </p><p>CONCLUSION: Our study suggests that Gal-3 can potentiate the PD-1/PD-L1 immune axis and potentially contribute to the immunosuppressive signalling mechanisms within the tumor microenvironment. In addition, Gal-3 prevents atezolizumab and pembrolizumab target engagement with their respective immune checkpoint receptors. Reversal of this effect with the clinical candidate GB1211 offers a potential enhancing combination therapeutic with anti-PD-1 and -PD-L1 blocking antibodies.</p>}},
author = {{Mabbitt, Joseph and Holyer, Ian D and Roper, James A and Nilsson, Ulf J and Zetterberg, Fredrik R and Vuong, Lynda and Mackinnon, Alison C and Pedersen, Anders and Slack, Robert J}},
issn = {{1664-3224}},
keywords = {{Animals; Mice; Galectin 3; Antibodies, Blocking; Antibodies, Monoclonal, Humanized/pharmacology}},
language = {{eng}},
publisher = {{Frontiers Media S. A.}},
series = {{Frontiers in Immunology}},
title = {{Resistance to anti-PD-1/anti-PD-L1 : galectin-3 inhibition with GB1211 reverses galectin-3-induced blockade of pembrolizumab and atezolizumab binding to PD-1/PD-L1}},
url = {{http://dx.doi.org/10.3389/fimmu.2023.1250559}},
doi = {{10.3389/fimmu.2023.1250559}},
volume = {{14}},
year = {{2023}},
}