Pancreatic ductal adenocarcinoma (PDA) remains one of the most lethal tumor types, with extremely low survival rates due to late diagnosis and resistance to standard therapies. A more comprehensive ...understanding of the complexity of PDA pathobiology, and especially of the role of the tumor microenvironment in disease progression, should pave the way for therapies to improve patient response rates. In this study, we identify galectin-1 (Gal1), a glycan-binding protein that is highly overexpressed in PDA stroma, as a major driver of pancreatic cancer progression. Genetic deletion of Gal1 in a Kras-driven mouse model of PDA (Ela-Kras
G12V
p53
−/−) results in a significant increase in survival through mechanisms involving decreased stroma activation, attenuated vascularization, and enhanced T cell infiltration leading to diminished metastasis rates. In a human setting, human pancreatic stellate cells (HPSCs) promote cancer proliferation, migration, and invasion via Gal1-driven pathways. Moreover, in vivo orthotopic coinjection of pancreatic tumor cells with Gal1-depleted HPSCs leads to impaired tumor formation and metastasis in mice. Gene-expression analyses of pancreatic tumor cells exposed to Gal1 reveal modulation of multiple regulatory pathways involved in tumor progression. Thus, Gal1 hierarchically regulates different events implicated in PDA biology including tumor cell proliferation, invasion, angiogenesis, inflammation, and metastasis, highlighting the broad therapeutic potential of Gal1-specific inhibitors, either alone or in combination with other therapeutic modalities.
Combined Antiretroviral therapy (cART) suppresses HIV replication but fails to eradicate the virus, which persists in a small pool of long-lived latently infected cells. Immune activation and ...residual inflammation during cART are considered to contribute to viral persistence. Galectins, a family of β-galactoside-binding proteins, play central roles in host-pathogen interactions and inflammatory responses. Depending on their structure, glycan binding specificities and/or formation of distinct multivalent signaling complexes, different members of this family can complement, synergize, or oppose the function of others. Here, we identify a regulatory circuit, mediated by galectin-1 (Gal-1)–glycan interactions, that promotes reversal of HIV-1 latency in infected T cells. We found elevated levels of circulating Gal-1 in plasma from HIV-1-infected individuals, which correlated both with inflammatory markers and the transcriptional activity of the reservoir, as determined by unspliced-RNA (US-RNA) copy number. Proinflammatory extracellular vesicles (EVs) isolated from the plasma of HIV-infected individuals induced Gal-1 secretion by macrophages. Extracellularly, Gal-1 interacted with latently infected resting primary CD4+ T cells and J-LAT cells in a glycan-dependent manner and reversed HIV latency via activation of the nuclear factor κB (NF-κB). Furthermore, CD4+ T cells isolated from HIV-infected individuals showed increased HIV-1 transcriptional activity when exposed to Gal-1. Thus, by modulating reservoir dynamics, EV-driven Gal-1 secretion by macrophages links inflammation with HIV-1 persistence in cART-treated individuals. IMPORTANCE Antiretroviral therapy has led to a dramatic reduction in HIV-related morbidity and mortality. However, cART does not eradicate the virus, which persists in resting CD4+ T cells as the main viral reservoir, consequently requiring lifelong treatment. A major question is how the functional status of the immune system during antiretroviral therapy determines the activity and size of the viral reservoir. In this study, we identified a central role for galectin-1 (Gal-1), a glycan-binding protein released in response to extracellular vesicles (EVs), in modulating the activity of HIV reservoir, thus shaping chronic immune activation in HIV-infected patients. Our work unveils a central role of Gal-1 in linking chronic immune activation and reservoir dynamics, highlighting new therapeutic opportunities in HIV infection.
Galectins, a family of glycan-binding proteins, influence tumor progression by modulating interactions between tumor, endothelial, stromal, and immune cells. Despite considerable progress in ...identifying the roles of individual galectins in tumor biology, an integrated portrait of the galectin network in different tumor microenvironments is still missing. We undertook this study to analyze the "galectin signature" of the human prostate cancer microenvironment with the overarching goal of selecting novel-molecular targets for prognostic and therapeutic purposes. In examining androgen-responsive and castration-resistant prostate cancer cells and primary tumors representing different stages of the disease, we found that galectin-1 (Gal-1) was the most abundantly expressed galectin in prostate cancer tissue and was markedly upregulated during disease progression. In contrast, all other galectins were expressed at lower levels: Gal-3, -4, -9, and -12 were downregulated during disease evolution, whereas expression of Gal-8 was unchanged. Given the prominent regulation of Gal-1 during prostate cancer progression and its predominant localization at the tumor-vascular interface, we analyzed the potential role of this endogenous lectin in prostate cancer angiogenesis. In human prostate cancer tissue arrays, Gal-1 expression correlated with the presence of blood vessels, particularly in advanced stages of the disease. Silencing Gal-1 in prostate cancer cells reduced tumor vascularization without altering expression of other angiogenesis-related genes. Collectively, our findings identify a dynamically regulated "galectin-specific signature" that accompanies disease evolution in prostate cancer, and they highlight a major role for Gal-1 as a tractable target for antiangiogenic therapy in advanced stages of the disease.
The vast range and complexity of glycan structures and their dynamic variations in health and disease have presented formidable challenges toward understanding the biological significance of these ...molecules. Despite these limitations, compelling evidence highlights a major role for galectins, a family of soluble glycan-binding proteins, as endogenous decoders that translate glycan-containing information into a broad spectrum of cellular responses by modulating receptor clustering, reorganization, endocytosis, and signaling. Here, we underscore pioneer findings and recent advances in understanding the biology of galectin–glycan interactions in myeloid, lymphoid, and endothelial compartments, highlighting important pathways by which these multivalent complexes control immune and vascular programs. Implementation of novel glycoanalytical approaches, as well as the use of genetically engineered cell and organism models, have allowed glycans and galectins to be explored across a range of cellular processes.
Galectins initiate, amplify, or attenuate immune and vascular signaling programs by reprogramming the function of glycosylated receptors in the absence or presence of their canonical ligands.
Galectin–glycan interactions act by modulating clustering, reorganization, distancing, internalization, and signaling of relevant receptors in myeloid, lymphoid, and endothelial compartments.
A dynamic glycosylation signature on target cells controls the immunoregulatory and proangiogenic activities of galectins.
Galectins have emerged as novel therapeutic targets in autoimmunity, inflammation, fibrosis, and cancer, and their expression may confer resistance to anticancer therapies.
Although immune checkpoint blockers have yielded significant clinical benefits in patients with different malignancies, the efficacy of these therapies is still limited. Here, we show that disruption ...of transmembrane protein 176B (TMEM176B) contributes to CD8+ T cell-mediated tumor growth inhibition by unleashing inflammasome activation. Lack of Tmem176b enhances the antitumor activity of anti-CTLA-4 antibodies through mechanisms involving caspase-1/IL-1β activation. Accordingly, patients responding to checkpoint blockade therapies display an activated inflammasome signature. Finally, we identify BayK8644 as a potent TMEM176B inhibitor that promotes CD8+ T cell-mediated tumor control and reinforces the antitumor activity of both anti-CTLA-4 and anti-PD-1 antibodies. Thus, pharmacologic de-repression of the inflammasome by targeting TMEM176B may enhance the therapeutic efficacy of immune checkpoint blockers.
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•TMEM176B inhibits the NLRP3 inflammasome by controlling cytosolic Ca2+.•Lack of Tmem176b enhances antitumor immunity via the caspase-1/IL-1β pathway•Human tumors responding to immune checkpoint blockade display an inflammasome-activated signature•A TMEM176B inhibitor improves the antitumor activity of immune checkpoint blockade
Segovia et al. show that TMEM176B inhibits inflammasome activation and IL-1β cleavage by controlling cytosolic Ca2+ in dendritic cells and macrophages. Inhibition of TMEM176B enhances tumor infiltration by CD8+ T cells and improves the antitumor activity of immune checkpoint blockers.
Hypoxia, angiogenesis, and immunosuppression have been proposed to be interrelated events that fuel tumor progression and impair the clinical effectiveness of anti-tumor therapies. Here we present ...new mechanistic data highlighting the role of hypoxia in fine-tuning CD8 T cell exhaustion
, in an attempt to reconcile seemingly opposite evidence regarding the impact of hypoxia on functional features of exhausted CD8 T cells. Focusing on the recently characterized terminally-differentiated and progenitor exhausted CD8 T cells, we found that both hypoxia and its regulated mediator, vascular endothelial growth factor (VEGF)-A, promote the differentiation of PD-1
TIM-3
CXCR5
terminally exhausted-like CD8 T cells at the expense of PD-1
TIM-3
progenitor-like subsets without affecting tumor necrosis factor (TNF)-α and interferon (IFN)-γ production or granzyme B (GZMB) expression by these subpopulations. Interestingly, hypoxia accentuated the proangiogenic secretory profile in exhausted CD8 T cells. VEGF-A was the main factor differentially secreted by exhausted CD8 T cells under hypoxic conditions. In this sense, we found that VEGF-A contributes to generation of terminally exhausted CD8 T cells during
differentiation. Altogether, our findings highlight the reciprocal regulation between hypoxia, angiogenesis, and immunosuppression, providing a rational basis to optimize synergistic combinations of antiangiogenic and immunotherapeutic strategies, with the overarching goal of improving the efficacy of these treatments.
Every day, more than one million people worldwide acquire a sexually transmitted infection (STI). This public health problem has a direct effect on women's reproductive and sexual health as STIs can ...cause irreversible damage to fertility and can have negative consequences associated with discrimination and social exclusion. Infection with one sexually transmitted pathogen predisposes to co-infection with others, suggesting the existence of shared pathways that serve as molecular links between these diseases. Galectins, a family of β-galactoside-binding proteins, have emerged as endogenous mediators that facilitate cell-surface binding, internalization and cell invasion of many sexually transmitted pathogens, including Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis, Candida albicans, HIV and herpes simplex virus. The ability of certain galectins to dimerize or form multimeric complexes confers the capacity to interact simultaneously with glycosylated ligands on both the pathogen and the cervico-vaginal tissue on these proteins. Galectins can act as a bridge by engaging glycans from the pathogen surface and glycosylated receptors from host cells, which is a mechanism that has been shown to be shared by several sexually transmitted pathogens. In the case of viruses and obligate intracellular bacteria, binding to the cell surface promotes pathogen internalization and cell invasion. Inflammatory responses that occur in cervico-vaginal tissue might trigger secretion of galectins, which in turn control the establishment, evolution and severity of STIs. Thus, galectin-targeted therapies could potentially prevent or decrease STIs caused by a diverse array of pathogenic microorganisms; furthermore, anti-galectin agents might reduce treatment costs of STIs and reach the most vulnerable populations.
•Galectins influence tumor progression by reprogramming the tumor microenvironment.•Galectins are expressed and released by both tumoral and non-tumoral cells.•Galectins and glycans modulate ...fibroblast, endothelial and immune cell programs.•Galectins control tumor immunity by targeting lymphoid and myeloid cell function.
Tumor cells corrupt surrounding normal cells instructing them to support proliferative, pro-angiogenic and immunosuppressive networks that favor tumorigenesis and metastasis. This dynamic cross-talk is sustained by a range of intracellular signals and extracellular mediators produced by both tumoral and non-tumoral cells. Galectins –whether secreted or intracellularly expressed– play central roles in the tumorigenic process by delivering regulatory signals that contribute to reprogram fibroblasts, endothelial and immune cell programs. Through glycosylation-dependent or independent mechanisms, these endogenous lectins control a variety of cellular events leading to tumor cell proliferation, survival, migration, inflammation, angiogenesis and immune escape. Here we discuss the role of galectin-driven pathways, particularly those activated in non-tumoral stromal cells, in modulating tumor progression.
Regulated glycosylation controls T cell processes, including activation, differentiation and homing by creating or masking ligands for endogenous lectins. Here we show that stimuli promoting T helper ...type 1 (TH1), TH2 or interleukin 17-producing T helper (TH-17) differentiation can differentially regulate the glycosylation pattern of T helper cells and modulate their susceptibility to galectin-1, a glycan-binding protein with anti-inflammatory activity. Although TH1- and TH-17-differentiated cells expressed the repertoire of cell surface glycans critical for galectin-1-induced cell death, TH2 cells were protected from galectin-1 through differential sialylation of cell surface glycoproteins. Consistent with those findings, galectin-1-deficient mice developed greater TH1 and TH-17 responses and enhanced susceptibility to autoimmune neuroinflammation. Our findings identify a molecular link among differential glycosylation of T helper cells, susceptibility to cell death and termination of the inflammatory response.
Abstract Galectin-1 (Gal-1), a member of a highly conserved family of animal lectins, binds to the common disaccharide Galβ(1-4)-GlcNAc on both N - and O -glycans decorating cell surface ...glycoconjugates. Current evidence supports a role for Gal-1 in the pathophysiology of multiple sclerosis (MS), one of the most prevalent chronic inflammatory diseases. Previous studies showed that Gal-1 exerts neuroprotective effects by promoting microglial deactivation in a model of autoimmune neuroinflammation and induces axonal regeneration in spinal cord injury. Seeking a model that could link demyelination, oligodendrocyte (OLG) responses and microglial activation, here we used a lysolecithin (LPC)-induced demyelination model to evaluate the ability of Gal-1 to preserve myelin without taking part in T-cell modulation. Gal-1 treatment after LPC-induced demyelination promoted a significant decrease in the demyelinated area and fostered more efficient remyelination, concomitantly with an attenuated oligodendroglial progenitor response reflecting less severe myelination damage. These results were accompanied by a decrease in the area of microglial activation with a shift toward an M2-polarized microglial phenotype and diminished astroglial activation. In vitro studies further showed that, mechanistically, Gal-1 targets activated microglia, promoting an increase in their myelin phagocytic capacity and their shift toward an M2 phenotype, and leads to oligodendroglial differentiation. Therefore, this study supports the use of Gal-1 as a potential treatment for demyelinating diseases such as MS.
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