Obesity-induced galectin-9 is a therapeutic target in B-cell acute lymphoblastic leukemia

Lee, Mi-Young; Hamilton, Jamie A.G.; Ross, Anthony J; Michael, Langston; Rupji, Manali; Dwivedi, Bhakti; Raikar, Sunil S.; Boss, Jeremy M.; Scharer, Christopher D.; Graham, Douglas K.; DeRyckere, Deborah; Porter, Christopher C.; Henry, Curtis J.

doi:10.1038/s41467-022-28839-y

Cited by 15 publications

(18 citation statements)

References 83 publications

(73 reference statements)

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“…Besides improving T cell responses, antibody-mediated targeting of Galectin-9 on B-ALL cells induces DNA damage, alters cell cycle progression, and promotes apoptosis in vitro and significantly extends the survival of mice with aggressive B-ALL (Lee et al, 2022). Accordingly, we cannot exclude that a similar direct activity on CLL cells contributes to the delayed leukemia development in TCL1 mice.…”

Section: Discussionmentioning

confidence: 99%

High-dimensional single-cell definition of CLL T cells identifies Galectin-9 as novel immunotherapy target

Cid

Wong

Botana

et al. 2022

Preprint

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Failure of immunotherapy after applying checkpoint inhibitors or CAR-T cells is linked to T cell exhaustion. Here, we explored the T cell landscape in chronic lymphocytic leukemia (CLL) by single-cell omics analyses of blood, bone marrow and lymph node samples of patients and spleen samples of a CLL mouse model. By single-cell RNA-sequencing, mass cytometry (CyTOF), and multiplex image analysis of tissue microarrays, we defined the spectrum of phenotypes and transcriptional programs of T cells and and their differentiation state trajectories. We identified disease-specific accumulation of distinct regulatory T cell subsets and T cells harboring an exhausted phenotype exclusively in the CLL lymph node tissue. Integration of TCR data revealed a clonal expansion of CD8+ precursor exhausted T cells, suggesting their reactivity for CLL cells. Interactome analyses identified the TIM3 ligand Galectin-9 as novel immunoregulatory molecule in CLL. Blocking of Galectin-9 in CLL-bearing mice slowed down disease development and reduced the number of TIM3 expressing T cells. Galectin-9 expression correlated with shorter survival of CLL patients. Thus, Galectin-9 contributes to immune escape in CLL and represents a novel target for immunotherapy.

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Section: Discussionmentioning

confidence: 99%

High-dimensional single-cell definition of CLL T cells identifies Galectin-9 as novel immunotherapy target

Cid

Wong

Botana

et al. 2022

Preprint

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“…Adipocytes have been shown to induce chemoresistance by both directly sequestering chemotherapeutic agents and by increasing leukemic blasts fitness through the production of pro- and anti-inflammatory adipokines, fueling the leukemic cells with free fatty acids and promoting oxidative phosphorylation ( 64 , 65 ). The upregulation of Galectin-9 by adipokines is responsible for several of these effects with preliminary studies implicating Galectin-9 as a therapeutic target ( 66 ). Interestingly, the role of adipocytes has been shown to alter dynamically during treatment, with a particular role in promoting a quiescent chemo-resistant state in regenerating bone marrow.…”

Section: Epigenetic Adaptation To Extracellular Cues Underlies Tumor ...mentioning

confidence: 99%

The role of microenvironment in the initiation and evolution of B-cell precursor acute lymphoblastic leukemia

Garcia-Gimenez

Richardson²

2023

Front. Oncol.

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B cell precursor acute lymphoblastic leukemia (BCP-ALL) is a malignant disorder of immature B lineage immune progenitors and is the commonest cancer in children. Despite treatment advances it remains a leading cause of death in childhood and response rates in adults remain poor. A preleukemic state predisposing children to BCP-ALL frequently arises in utero, with an incidence far higher than that of transformed leukemia, offering the potential for early intervention to prevent disease. Understanding the natural history of this disease requires an appreciation of how cell-extrinsic pressures, including microenvironment, immune surveillance and chemotherapy direct cell-intrinsic genetic and epigenetic evolution. In this review, we outline how microenvironmental factors interact with BCP-ALL at different stages of tumorigenesis and highlight emerging therapeutic avenues.

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“…Galectin-9 expression is distributed in various tumor organs, including the liver, small intestine, thymus, kidney, spleen, lung, heart, skeletal muscle [ 14 ], brain [ 66 ], placenta, pancreas, prostate, and colon [ 67 ]. Among them, predominantly expressing cells include leukocytes [ 68 , 69 , 70 ], which are responsible for innate and acquired immunity [ 71 ], thymocytes [ 14 ], activated endothelial cells [ 72 , 73 ], and fibroblasts stimulated by interferons [ 74 ]. Among malignant tissues, galectin-9 expression on the cell surface has been reported to be reduced in hepatocellular carcinoma (HCC) as well as in other solid tumors, such as prostate cancer [ 75 ], cervical cancer [ 76 ], and skin cancer [ 77 , 78 ].…”

Section: Galectin-9mentioning

confidence: 99%

Galectin-9 in Gastroenterological Cancer

Morishita

Oura

Tadokoro

et al. 2023

IJMS

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Immunochemotherapy has become popular in recent years. The detailed mechanisms of cancer immunity are being elucidated, and new developments are expected in the future. Apoptosis allows tissues to maintain their form, quantity, and function by eliminating excess or abnormal cells. When apoptosis is inhibited, the balance between cell division and death is disrupted and tissue homeostasis is impaired. This leads to dysfunction and the accumulation of genetically abnormal cells, which can contribute to carcinogenesis. Lectins are neither enzymes nor antibodies but proteins that bind sugar chains. Among soluble endogenous lectins, galectins interact with cell surface sugar chains outside the cell to regulate signal transduction and cell growth. On the other hand, intracellular lectins are present at the plasma membrane and regulate signal transduction by regulating receptor–ligand interactions. Galectin-9 expressed on the surface of thymocytes induces apoptosis of T lymphocytes and plays an essential role in immune self-tolerance by negative selection in the thymus. Furthermore, the administration of extracellular galectin-9 induces apoptosis of human cancer and immunodeficient cells. However, the detailed pharmacokinetics of galectin-9 in vivo have not been elucidated. In addition, the cell surface receptors involved in galectin-9-induced apoptosis of cancer cells have not been identified, and the intracellular pathways involved in apoptosis have not been fully investigated. We have previously reported that galectin-9 induces apoptosis in various gastrointestinal cancers and suppresses tumor growth. However, the mechanism of galectin-9 and apoptosis induction in gastrointestinal cancers and the detailed mechanisms involved in tumor growth inhibition remain unknown. In this article, we review the effects of galectin-9 on gastrointestinal cancers and its mechanisms.

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Obesity-induced galectin-9 is a therapeutic target in B-cell acute lymphoblastic leukemia

Cited by 15 publications

References 83 publications

High-dimensional single-cell definition of CLL T cells identifies Galectin-9 as novel immunotherapy target

High-dimensional single-cell definition of CLL T cells identifies Galectin-9 as novel immunotherapy target

The role of microenvironment in the initiation and evolution of B-cell precursor acute lymphoblastic leukemia

Galectin-9 in Gastroenterological Cancer

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