Tumor associated macrophages-programmed core immunosuppressive microenvironments via Galectin-1 in breast cancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA836797 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR19155539_1.fastq.gz | Fastqsanger.gz | |||
| SRR19155539_2.fastq.gz | Fastqsanger.gz | |||
| SRR19155540_1.fastq.gz | Fastqsanger.gz | |||
| SRR19155540_2.fastq.gz | Fastqsanger.gz |
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Project description:There has been considerable interest in therapeutic targeting of tumor-associated macrophages (TAMs) mainly by depleting or repolarizing them toward anti-tumoral phenotypes. However, a core mediator co-opted for TAMs-mediated remodeling of tumor microenvironment remains poorly understood. Here, to dissect TAMs-mediated early microenvironment, we performed single-cell RNA sequencing of TAMs-enriched and -depleted mouse breast tumor at the early stages of progression, before detectable change in tumor growth appeared. We found that early intratumoral accumulation of TAMs endowed cancer cells with invasive properties to promote early dissemination and dampened antitumoral T cell responses. Accordingly, TAMs-depleted tumor using clodronate displayed a decreased epithelial-to mesenchymal transition (EMT) signature of cancer cells and harbored a distinct transcriptome associated with CD8+ T cells activation. Furthermore, we identified a role of Galectin-1 (Gal-1) as a molecular checkpoint in TAMs-induced CD8+ T cell exhaustion. Gal-1 inhibition reversed immune suppression via reinvigoration of CD8+ T cells, thus impairing tumor growth and boosting the efficacy of immune checkpoint inhibitor in a breast tumor model. These results provide a comprehensive insight into the early-programmed microenvironment by TAMs and reveal an immune evasion mechanism that could be targeted by Gal-1 to unleash antitumor immune responses.
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Project description:Conduct gene profiling experiment from a melanoma cell line which silenced galectin-3 gene expression to understand different phenotypic properties observed during tumor growth. A melanoma cell line which silenced galectin-3 gene expression was obtained. This cell line was used in overexpression experiments, using a galectin-3 coding plasmid. Both galectin-3 negative and positive cells were obtained in syngeneic wild type and galectin-3 knockout mice. Altogether, we had evidence that while galectin-3 derived from the tumor cells impaired tumor growth, galectin-3 derived from stromal cells apparently favored tumor growth. Angiogenic response within tumors derived from galectin-3 expressing melanoma cells was delayed as compared to control conditions. Cells recruited to these distinct microenvironments seem to control tumor growth. Gene profiling of this tissue will allow for an integrative view of the process that was somehow orchestrated by galectin-3.
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Project description:Hyperactive angiogenesis contributes to the immunosuppressive microenvironment important for immunotherapy, and LGALS1-encoed galectin-1 can trigger vascular signaling programs and mediate anti-angiogenic treatment response. However, the mechanism of galectin-1 regulation of angiogenesis is poorly understood. Previous mRNA interactome studies suggested that galectin-1 associated with mRNAs. In this study, we applied the iRIP-seq methodology, an unbiased genome-wide approach to study the RNA binding profiles of galectin-1. The results demonstrate that galectin-1 interacted with a large population of mRNAs with a preferred location towards stop codon, and preferred motifs of UGCA/UGGA and GAGCAG motifs. Galectin-1-bound mRNAs are enriched in cell cycle control and diverse basic biological processes, including its previously reported protein targets H-Ras and also T cell receptors TLR6. Glectin-1 significantly binds to genes in angiogenesis, which included the key pro-angiogenic growth factor VEGFA, angiogenic regulators EGR1 and LAMA5, suggesting that galectin-1 may regulate via its mRNA binding activity. The presented results uncover an previously unrecognized mRNA binding activity of galectin-1; further pursue of this activity could lead to knowledge important for developing therapeutic strategies against cancer and other diseases involved in aberrant angiogenesis.
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Project description:Dr. Panjwani's laboratory is focusing on the mechanism by which galectins-3 and 7 mediate corneal epithelial cell migration. Recently published studies, that we have confirmed and expended on in our laboratory, clearly demonstrate that galectin-3 mediates angiogenesis in vitro and in vivo. More interestingly we have found that bFGF- and VEGF-mediated angiogenesis can be inhibited by galectin-3 inhibitors, which suggests an important role of carbohydrate recognition systems in the process of angiogenesis. In an effort to characterize the role of carbohydrate recognition system in angiogenesis, we are interested to evaluate and compare the glyco-gene expression profile of endothelial cells stimulated with VEGF, bFGF and galectin-3 at time and concentration at which, the compounds stimulate angiogenesis in vitro. RNA preparations of Galectin-3, VEGF, bFGF, Media Control biological replicates were sent to Microarray Core (E). The RNA was amplified, labeled, and hybridized to GLYCO_v3 microarrays.
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Project description:The goal of this study was to examine differences in gene expression of tumor specific CD8 T cells in an in vivo tumor mouse model after inhibition of galectin-3 protein expression by genetic knockout. Galectin-3 is thought to modulate CD8 T cell response by cross-linking cell surface glycoproteins Galectin-3 is a 31 kD carbohydrate-binding lectin that is over-expressed by many human malignancies. It also modulates T cell responses through a diverse array of mechanisms including induction of apoptosis, TCR cross linking in CD8+ T cells, and T cell receptor (TCR) down regulation in CD4+ T cells. We found that patients responding to a granulocyte-macrophage colony-stimulating factor (GM-CSF) secreting allogeneic pancreatic tumor vaccine developed post immunization antibody responses to galectin-3 on a proteomic screen. We used the HER-2/neu (neu-N) transgenic mouse model to study galectin-3 binding on adoptively transferred high avidity neu-specific CD8+ T cells derived from TCR transgenic mice. Here, we show that galectin-3 binds preferentially to activated antigen-committed CD8+ T cells only in the tumor microenvironment (TME). Galectin-3 deficient mice exhibit improved CD8+ T cell effector function and increased expression of several inflammatory genes when compared with wild type (WT) mice. We also show that galectin-3 binds to LAG-3, and LAG-3 expression is necessary for galectin-3 mediated suppression of CD8+ T cells in vitro. Lastly, galectin-3 deficient mice have significantly elevated levels of circulating plasmacytoid dendritic cells (pDCs), which are superior to conventional dendritic cells (cDCs) in activating CD8+ T cells. Binding of galectin-3 to cell-surface glycoproteins on immune cells suppresses a pro-inflammatory immune response. Thus, inhibiting galectin-3 in conjunction with CD8+ T cell directed immunotherapies should enhance the tumor specific immune response. 3 different experimental groups were studied. Galectin-3 WT CD8 T cells adoptively transferred into Galectin-3 WT mice, galectin-3 WT CD8 T cells transferred into galectin-3 KO mice, and finally galectin-3 KO CD8 T cells transferred into galectin-3 KO mice. Galectin-3 WT CD8 T cells transferred into Galectin-3 WT mice were used as the reference group. Four biological replicates were submitted for each group, and adoptively transfered CD8 T cells were isolated 5 days post-adoptive transfer into tumor-bearing mice treated with a whole cell GM-CSF secreting vaccine. Cells were purified by cell sorting on the Thy1.2 surface marker.
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Project description:The goal of this study was to examine differences in gene expression of tumor specific CD8 T cells in an in vivo tumor mouse model after inhibition of galectin-3 protein expression by genetic knockout. Galectin-3 is thought to modulate CD8 T cell response by cross-linking cell surface glycoproteins Galectin-3 is a 31 kD carbohydrate-binding lectin that is over-expressed by many human malignancies. It also modulates T cell responses through a diverse array of mechanisms including induction of apoptosis, TCR cross linking in CD8+ T cells, and T cell receptor (TCR) down regulation in CD4+ T cells. We found that patients responding to a granulocyte-macrophage colony-stimulating factor (GM-CSF) secreting allogeneic pancreatic tumor vaccine developed post immunization antibody responses to galectin-3 on a proteomic screen. We used the HER-2/neu (neu-N) transgenic mouse model to study galectin-3 binding on adoptively transferred high avidity neu-specific CD8+ T cells derived from TCR transgenic mice. Here, we show that galectin-3 binds preferentially to activated antigen-committed CD8+ T cells only in the tumor microenvironment (TME). Galectin-3 deficient mice exhibit improved CD8+ T cell effector function and increased expression of several inflammatory genes when compared with wild type (WT) mice. We also show that galectin-3 binds to LAG-3, and LAG-3 expression is necessary for galectin-3 mediated suppression of CD8+ T cells in vitro. Lastly, galectin-3 deficient mice have significantly elevated levels of circulating plasmacytoid dendritic cells (pDCs), which are superior to conventional dendritic cells (cDCs) in activating CD8+ T cells. Binding of galectin-3 to cell-surface glycoproteins on immune cells suppresses a pro-inflammatory immune response. Thus, inhibiting galectin-3 in conjunction with CD8+ T cell directed immunotherapies should enhance the tumor specific immune response.
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