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Review

Modulation of the Gal-9/TIM-3 Immune Checkpoint with α-Lactose. Does Anomery of Lactose Matter?

1
OncoWitan, Scientific Consulting Office, 59290 Lille, France
2
University of Lille, CNRS, Inserm, CHU Lille, UMR9020—UMR1277—Canther—Cancer Heterogeneity, Plasticity and Resistance to Therapies, 59000 Lille, France
*
Author to whom correspondence should be addressed.
Academic Editor: Jason Roszik
Cancers 2021, 13(24), 6365; https://doi.org/10.3390/cancers13246365
Received: 15 November 2021 / Revised: 8 December 2021 / Accepted: 16 December 2021 / Published: 18 December 2021
(This article belongs to the Special Issue New Targets and Therapies of Acute Myeloid Leukemia)
The disaccharide lactose is a common excipient in pharmaceutical products. In addition, the two anomers α- and β-lactose can exert immuno-modulatory effects. α-Lactose functions as a major regulator of the T-cell immunoglobulin mucin-3 (Tim-3)/Galectin-9 (Gal-9) immune checkpoint, through direct binding to the β-galactoside-binding lectin galectin-9. The blockade of TIM-3 with monoclonal antibodies or small molecules represents a promising approach to combat onco-hematological diseases, in particular myelodysplastic syndromes, and acute myeloid leukemia. Alternatively, the activity of the checkpoint can be modulated via targeting of Gal-9 with both α- and β-lactose. In fact, lactose is a quasi-pan-galectin ligand, capable of modulating the functions of most of the 16 galectin molecules. This review discusses the capacity of lactose and Gal-9 to modulate the TIM-3/Gal-9 and PD-1/PD-L1 immune checkpoints in oncology. The immuno-regulatory roles of lactose and Gal-9 are highlighted.
The disaccharide lactose is an excipient commonly used in pharmaceutical products. The two anomers, α- and β-lactose (α-L/β-L), differ by the orientation of the C-1 hydroxyl group on the glucose unit. In aqueous solution, a mutarotation process leads to an equilibrium of about 40% α-L and 60% β-L at room temperature. Beyond a pharmaceutical excipient in solid products, α-L has immuno-modulatory effects and functions as a major regulator of TIM-3/Gal-9 immune checkpoint, through direct binding to the β-galactoside-binding lectin galectin-9. The blockade of the co-inhibitory checkpoint TIM-3 expressed on T cells with anti-TIM-3 antibodies represents a promising approach to combat different onco-hematological diseases, in particular myelodysplastic syndromes and acute myeloid leukemia. In parallel, the discovery and development of anti-TIM-3 small molecule ligands is emerging, including peptides, RNA aptamers and a few specifically designed heterocyclic molecules. An alternative option consists of targeting the different ligands of TIM-3, notably Gal-9 recognized by α-lactose. Modulation of the TIM-3/Gal-9 checkpoint can be achieved with both α- and β-lactose. Moreover, lactose is a quasi-pan-galectin ligand, capable of modulating the functions of most of the 16 galectin molecules. The present review provides a complete analysis of the pharmaceutical and galectin-related biological functions of (α/β)-lactose. A focus is made on the capacity of lactose and Gal-9 to modulate both the TIM-3/Gal-9 and PD-1/PD-L1 immune checkpoints in oncology. Modulation of the TIM-3/Gal-9 checkpoint is a promising approach for the treatment of cancers and the role of lactose in this context is discussed. The review highlights the immuno-regulatory functions of lactose, and the benefit of the molecule well beyond its use as a pharmaceutical excipient. View Full-Text
Keywords: lactose; galectin-9; PD-1/PD-L1; TIM-3; soluble PD-L1; immune checkpoint; cancer lactose; galectin-9; PD-1/PD-L1; TIM-3; soluble PD-L1; immune checkpoint; cancer
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MDPI and ACS Style

Bailly, C.; Thuru, X.; Quesnel, B. Modulation of the Gal-9/TIM-3 Immune Checkpoint with α-Lactose. Does Anomery of Lactose Matter? Cancers 2021, 13, 6365. https://doi.org/10.3390/cancers13246365

AMA Style

Bailly C, Thuru X, Quesnel B. Modulation of the Gal-9/TIM-3 Immune Checkpoint with α-Lactose. Does Anomery of Lactose Matter? Cancers. 2021; 13(24):6365. https://doi.org/10.3390/cancers13246365

Chicago/Turabian Style

Bailly, Christian, Xavier Thuru, and Bruno Quesnel. 2021. "Modulation of the Gal-9/TIM-3 Immune Checkpoint with α-Lactose. Does Anomery of Lactose Matter?" Cancers 13, no. 24: 6365. https://doi.org/10.3390/cancers13246365

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