Galectin inhibitory disaccharides promote tumour immunity in a breast cancer model

Stannard, Kimberley; Collins, P.; Ito, Koichi; Sullivan, Elizabeth; Scott, Stacy A.; Gabutero, Elwyn; Grice, I. Darren; Low, Pauline; Nilsson, Ulf J.; Leffler, Hakon; Blanchard, Helen; Ralph, Stephen John

doi:10.1016/j.canlet.2010.08.005

Cited by 91 publications

(84 citation statements)

References 77 publications

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“…Several therapeutic strategies have been proposed to block the detrimental effects of Gal1-glycan interactions; however, none of these strategies are fully specific for Gal1. For example, thiodigalatoside, a non-metabolizable small disaccharide that binds Gal1, prevents some tumor-promoting effects of this endogenous lectin, including angiogenesis and immune escape (40,41,49,50). However, this compound also binds and inhibits the action of other members of the galectin family through blockade of the carbohydrate-recognition domain (49,50).…”

Section: Discussionmentioning

confidence: 99%

“…For example, thiodigalatoside, a non-metabolizable small disaccharide that binds Gal1, prevents some tumor-promoting effects of this endogenous lectin, including angiogenesis and immune escape (40,41,49,50). However, this compound also binds and inhibits the action of other members of the galectin family through blockade of the carbohydrate-recognition domain (49,50). With the long-term goal of translating basic findings into potential clinical approaches, we envisage that specifically blocking Gal1 in the tumor microenvironment (e.g., using an anti-Gal1 neutralizing mAb; ref.…”

Section: Discussionmentioning

confidence: 99%

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Targeting Galectin-1 Overcomes Breast Cancer-Associated Immunosuppression and Prevents Metastatic Disease

et al. 2013

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Galectin-1 (Gal1), an evolutionarily conserved glycan-binding protein, contributes to the creation of an immunosuppressed microenvironment at sites of tumor growth. In spite of considerable progress in elucidating its role in tumor-immune escape, the mechanisms underlying the inhibitory functions of Gal1 remain obscure. Here, we investigated the contribution of tumor Gal1 to tumor growth, metastasis, and immunosuppression in breast cancer. We found that the frequency of Gal1 þ cells in human breast cancer biopsies correlated positively with tumor grade, while specimens from patients with benign hyperplasia showed negative or limited Gal1 staining. To examine the pathophysiologic relevance of Gal1 in breast cancer, we used the metastatic mouse mammary tumor 4T1, which expresses and secretes substantial amounts of Gal1. Silencing Gal1 expression in this model induced a marked reduction in both tumor growth and the number of lung metastases. This effect was abrogated when mice were inoculated with wild-type 4T1 tumor cells in their contralateral flank, suggesting involvement of a systemic modulation of the immune response. Gal1 attenuation in 4T1 cells also reduced the frequency of CD4cells within the tumor, draining lymph nodes, spleen, and lung metastases. Further, it abrogated the immunosuppressive function of T reg cells and selectively lowered the expression of the T-cell regulatory molecule LAT (linker for activation of T cells) on these cells, disarming their suppressive activity. Taken together, our results offer a preclinical proof of concept that therapeutic targeting of Gal1 can overcome breast cancer-associated immunosuppression and can prevent metastatic disease. Cancer Res; 73(3); 1107-17. Ó2012 AACR.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Targeting Galectin-1 Overcomes Breast Cancer-Associated Immunosuppression and Prevents Metastatic Disease

et al. 2013

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“…83 Administering TDG following prophylactic vaccination with a tumor-specific antigen improved survival following tumor challenge in a murine breast cancer model. 84 In addition, delivery of TDG increased the number of CD4 þ and CD8 þ T cells in peripheral blood, as well as the number of CD3 þ T cells within metastases, ultimately leading to a reduction in pulmonary metastasis in murine breast and colon cancer models. 85 Alternatively, lactoside derivatives can reduce HIV binding to target cells in vitro by inhibiting galectin-1 binding to CD4 þ T cells, 86 suggesting their potential for disrupting host-virus interactions that are a rate-limiting step in HIV infection.…”

Section: Inhibiting Galectin-t-cell Interactions To Maintain or Restomentioning

confidence: 99%

Engineering galectin–glycan interactions for immunotherapy and immunomodulation

Farhadi

Hudalla

2016

Exp Biol Med (Maywood)

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Galectins, a 15-member family of soluble carbohydrate-binding proteins, are receiving increasing interest as therapeutic targets for immunotherapy and immunomodulation due to their role as extracellular signals that regulate innate and adaptive immune cell phenotype and function. However, different galectins can have redundant, synergistic, or antagonistic signaling activity in normal immunological responses, such as resolution of inflammation and induction of antigen-specific tolerance. In addition, certain galectins can be hijacked to promote progression of immunopathologies, such as tumor immune privilege, metastasis, and viral infection, while others can inhibit these processes. Thus, eliciting a desired immunological outcome will likely necessitate therapeutics that can precisely enhance or inhibit particular galectin-glycan interactions. Multivalency is an important determinant of the affinity and specificity of natural galectin-glycan interactions, and is emerging as a key design element for therapeutics that can effectively manipulate galectin bioactivity. This minireview surveys current molecular and biomaterial engineering approaches to create therapeutics that can stabilize galectin multivalency or recapitulate natural glycan multivalency (i.e. ''the glycocluster effect''). In particular, we highlight examples of using natural and engineered multivalent galectins for immunosuppression and immune tolerance, with a particular emphasis on treating autoimmune diseases or avoiding transplant rejection. In addition, we present examples of multivalent inhibitors of galectin-glycan interactions to maintain or restore T-cell function, with a particular emphasis on promoting antitumor immunity. Finally, we discuss emerging opportunities to further engineer galectin-glycan interactions for immunotherapy and immunomodulation.

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“…Gal-1 importance in tumor microenvironment immunosuppression is also considered in treatment. As a matter of fact, Gal-1 inhibition as adjuvant with vaccine immunotherapy significantly reduces breast tumor progression in mice (Stannard et al, 2010).…”

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confidence: 99%

Glycans and Galectins: Sweet New Approaches in Pancreatic Cancer Diagnosis and Treatment

Martínez-Bosch¹,

Navarro²

2012

Pancreatic Cancer - Molecular Mechanism and Targets

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Galectin inhibitory disaccharides promote tumour immunity in a breast cancer model

Cited by 91 publications

References 77 publications

Targeting Galectin-1 Overcomes Breast Cancer-Associated Immunosuppression and Prevents Metastatic Disease

Targeting Galectin-1 Overcomes Breast Cancer-Associated Immunosuppression and Prevents Metastatic Disease

Engineering galectin–glycan interactions for immunotherapy and immunomodulation

Glycans and Galectins: Sweet New Approaches in Pancreatic Cancer Diagnosis and Treatment

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