Galectins as pivotal components in oncogenesis and immune exclusion in human malignancies

Kapetanakis, Nikiforos-Ioannis; Busson, P.

doi:10.3389/fimmu.2023.1145268

Cited by 12 publications

(14 citation statements)

References 166 publications

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“…Concerning galectin-2, a recent study demonstrated that it plays a crucial role in TNBC by contributing to the formation of an immunosuppressive microenvironment, possibly following the release of its form extracellular by the tumor cell ( 39 ). These observations add to prior studies establishing galectins as prime targets for improving the efficacy of immunotherapy within the tumor microenvironment ( 40 – 42 ). Galectin-2 has also been found in the cytosol and nuclei of gastric cancer cells ( 43 ).…”

Section: Where Are Galectins In Cancer Cells?supporting

confidence: 57%

Targeting intracellular galectins for cancer treatment

Nehmé,

St-Pierre

2023

Front. Immunol.

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Although considerable attention has been paid to the role of extracellular galectins in modulating, positively or negatively, tumor growth and metastasis, we have witnessed a growing interest in the role of intracellular galectins in response to their environment. This is not surprising as many galectins preferentially exist in cytosolic and nuclear compartments, which is consistent with the fact that they are exported outside the cells via a yet undefined non-classical mechanism. This review summarizes our most recent knowledge of their intracellular functions in cancer cells and provides some directions for future strategies to inhibit their role in cancer progression.

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Section: Where Are Galectins In Cancer Cells?supporting

confidence: 57%

Targeting intracellular galectins for cancer treatment

Nehmé,

St-Pierre

2023

Front. Immunol.

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“…In pancreatic cancer, the crucial role of CD44/TGFβ receptors (TβRI and TβRII) signalling is well admitted not only in epithelial-to-mesenchymal transition but also in the earlier ADM step. This hypothesis is very likely with regard to the ability of other galectins to bridge different receptors to promote carcinogenesis ( 70 – 72 ). The hypothesis that LGALS9 mediates TGFβ and CD44 signalling in KRAS-driven carcinogenesis will need further investigation.…”

Section: Discussionmentioning

confidence: 99%

A novel anti-galectin-9 immunotherapy limits the early progression of pancreatic neoplastic lesions in transgenic mice

Quilbe,

Mustapha,

Duchêne

et al. 2023

Front. Immunol.

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BackgroundPancreatic adenocarcinoma (PDAC) is a devastating disease with an urgent need for therapeutic innovation. Immune checkpoint inhibition has shown promise in a variety of solid tumors, but most clinical trials have failed to demonstrate clinical efficacy in PDAC. This low efficacy is partly explained by a highly immunosuppressive microenvironment, which dampens anti-tumor immunity through the recruitment or induction of immunosuppressive cells, particularly regulatory T cells (Tregs). In this context, our laboratory has developed a novel immunotherapeutic strategy aimed at inhibiting the suppressive activity of Tregs, based on a patented (EP3152234B1) monoclonal antibody (mAb) targeting galectin-9 (LGALS9).Materials and methodsCD4+ conventional T cells (TCD4 or Tconv), Treg ratio, and LGALS9 expression were analyzed by immunohistochemistry (IHC) and cytometry in blood and pancreas of K-rasLSL.G12D/+;Pdx-1-Cre (KC) and K-rasWildType (WT);Pdx1-Cre (WT) mice aged 4–13 months. Pancreatic intraepithelial neoplasm (PanIN) progression and grade were quantified using FIJI software and validated by pathologists. The anti-galectin-9 mAb was validated for its use in mice on isolated murine C57BL/6 Treg by immunofluorescence staining and cytometry. Its specificity and functionality were validated in proliferation assays on rLGALS9-immunosuppressed murine Tconv and in suppression assays between murine Treg and Tconv. Finally, 2-month-old KC mice were treated with anti-LGALS9 and compared to WT mice for peripheral and infiltrating TCD4, Treg, and PanIN progression.ResultsIHC and cytometry revealed a significant increase in LGALS9 expression and Treg levels in the blood and pancreas of KC mice proportional to the stages of precancerous lesions. Although present in WT mice, LGALS9 is expressed at a basal level with low and restricted expression that increases slightly over time, while Treg cells are few in number in their circulation and even absent from the pancreas over time. Using our anti-LGALS9 mAb in mice, it is shown that (i) murine Treg express LGALS9, (ii) the mAb could target and inhibit recombinant murine LGALS9, and (iii) neutralize murine Treg suppressive activity. Finally, the anti-LGALS9 mAb in KC mice reduced (i) LGALS9 expression in pancreatic cancer cells, (ii) the Treg ratio, and (iii) the total surface area and grade of PanIN.ConclusionWe demonstrate for the first time that an anti-LGALS9 antibody, by specifically targeting endogenous LGALS9 tumor and exogenous LGALS9 produced by Treg, was able to limit the progression of pancreatic neoplastic lesions in mice, opening up new prospects for its use as an immunotherapeutic tool in PDAC.

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“…The interacting partners of galectin-9 have been identified and are mainly expressed on the cell surface of different immune cells, including NK cells, effector T cells, Tregs, monocytes, macrophages, and neutrophils ( Table 2 and Figure 3 ). Galectin-9 studies have revealed an immunoregulation [ 105 ] within the TME. These molecules are displayed as transmembrane proteins that transduce signals from the cell surface to intracellular effectors to control immune cell proliferation, survival, and cytokine secretion [ 106 ].…”

Section: Human Galectinsmentioning

confidence: 99%

Chimera and Tandem-Repeat Type Galectins: The New Targets for Cancer Immunotherapy

Yan

Lee

et al. 2023

Biomolecules

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In humans, a total of 12 galectins have been identified. Their intracellular and extracellular biological functions are explored and discussed in this review. These galectins play important roles in controlling immune responses within the tumour microenvironment (TME) and the infiltration of immune cells, including different subsets of T cells, macrophages, and neutrophils, to fight against cancer cells. However, these infiltrating cells also have repair roles and are hijacked by cancer cells for pro-tumorigenic activities. Upon a better understanding of the immunomodulating functions of galectin-3 and -9, their inhibitors, namely, GB1211 and LYT-200, have been selected as candidates for clinical trials. The use of these galectin inhibitors as combined treatments with current immune checkpoint inhibitors (ICIs) is also undergoing clinical trial investigations. Through their network of binding partners, inhibition of galectin have broad downstream effects acting on CD8+ cytotoxic T cells, regulatory T cells (Tregs), Natural Killer (NK) cells, and macrophages as well as playing pro-inflammatory roles, inhibiting T-cell exhaustion to support the fight against cancer cells. Other galectin members are also included in this review to provide insight into potential candidates for future treatment(s). The pitfalls and limitations of using galectins and their inhibitors are also discussed to cognise their clinical application.

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Galectins as pivotal components in oncogenesis and immune exclusion in human malignancies

Cited by 12 publications

References 166 publications

Targeting intracellular galectins for cancer treatment

Targeting intracellular galectins for cancer treatment

A novel anti-galectin-9 immunotherapy limits the early progression of pancreatic neoplastic lesions in transgenic mice

Chimera and Tandem-Repeat Type Galectins: The New Targets for Cancer Immunotherapy

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