Target the MDSC of tumor in situ by MAPK signaling pathway inhibitor to promote tumor regression
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA641027 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12066751_1.fastq.gz | Fastqsanger.gz | |||
| SRR12066751_2.fastq.gz | Fastqsanger.gz | |||
| SRR12066752_1.fastq.gz | Fastqsanger.gz | |||
| SRR12066752_2.fastq.gz | Fastqsanger.gz | |||
| SRR12066753_1.fastq.gz | Fastqsanger.gz |
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Project description:Myeloid-derived suppressor cells (MDSCs) are myeloid precursors which exert potent immunosuppressive properties in cancer. Despite the extensive knowledge on mechanisms implicated in mobilization, recruitment and function of MDSCs, still their therapeutic targeting remains an unmet need in cancer immunotherapy suggesting that unappreciated mechanisms of MDSC-mediated suppression exist. Herein, we demonstrate an important role of NLRP3 inflammasome in the functional properties of MDSCs in tumor-bearing hosts. Specifically, Nlrp3-deficient mice exhibited reduced tumor growth compared to wild-type animals and induction of robust anti-tumor immunity, accompanied by re-wiring of the MDSC compartment. Interestingly, both monocytic (M-MDSCs) and granulocytic (G-MDSCs) subsets from Nlrp3-/- mice displayed impaired suppressive activity and demonstrated significant transcriptomic alterations supporting the loss-of-function and associated with metabolic re-programming. Finally, therapeutic targeting of NLRP3 inhibited tumor development and re-programmed the MDSC compartment. These findings propose that targeting NLRP3 in MDSCs could overcome tumor-induced tolerance and may provide new checkpoints of cancer immunotherapy.
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Project description:The study analyzed the PMN-MDSCs and M-MDSCs genetic expression difference in spleen and tumor in order to find out the key target molecules
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Project description:Myeloid derived suppressor cells (MDSC) playing the immune suppressive roles in tumor bearing host consists of two major subsets of granulocytic and monocytic cells. Granulocytic MDSC (G-MDSC) express CD11b+ Gr-1high Ly6G+ Ly6Clow and produce high level of reactive oxygen species (ROS). Interestingly, neutrophils are well known ROS producing cells during immune defensive process and share same surface markers with G-MDSC. These similar features always brought the fundamental questions what’s the difference between G-MDSC and neutrophils but it’s not yet proven clearly. In this study, we examined the gene expression of G-MDSC and neutrophils using Affymetrix microarray G-MDSC (CD11b+Ly6G+Ly6Clow) were purifed from splenocytes in EL4 lymphoma tumor bearing mice by positive selection of Ly6G using microbeads isolation. Neutrophils were purified from ascitic fluids induced after injection of milk protein, casein by negative selection of F4/80 and positive selection of Ly6G using microbeads isolation. Their RNA was extracted and gene expression was analyzed using Affymetrix microarray.
2011-03-10 | E-GEOD-24102 | biostudies-arrayexpress
Project description:Myeloid derived suppressor cells (MDSC) in the tumor microenvironment suppress T-cell mediated immune surveillance that clears tumor cells. As such, MDSC promote tumor growth. There are two subtypes of tumor MDSC, CD11b+Ly6ChiLy6G- monocytic MDSC (M-MDSC) , and CD11b+Ly6ClowLy6Ghigh granulocytic MDSC (G-MDSC). Cells with these markers also exist in the spleen of tumor bearing mice or in the spleen of mice with tissue-specific inflammation. Some have argued that the tumor MDSC is an activated version of the spleen MDSC, implying that they are similar to one another. Here we isolated the MDSC subtypes from the RM-1 tumors and from the spleen of mice with prostatic inflammation (n=4 per subtype per tissue, 16 total samples). We then analyzed RNA from these cells to determine how the transcript profile was altered by tissue location and MDSC subtype. Platform: Affymetrix Mouse Gene 1.0 ST v1 Genechip
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Project description:Tumor growth is associated with a profound alteration of myelopoiesis, leading to recruitment of immunosuppressive cells known as myeloid-derived suppressor cells (MDSCs). Analyzing the cytokines affecting myelo-monocytic differentiation produced by various experimental tumors, we found that GM-CSF, G-CSF, and IL-6 allowed a rapid generation of MDSCs from precursors present in mouse and human bone marrow (BM). BM-MDSCs induced by GM-CSF+IL-6 possessed the highest tolerogenic activity, as revealed by the ability to impair the priming of IFN- -producing CD8+ T cells upon in vivo adoptive transfer. Moreover, adoptive transfer of syngeneic, GM-CSF+IL-6-conditioned MDSCs to diabetic mice transplanted with allogeneic pancreatic islets resulted in long term acceptance of the allograft and correction of the diabetic status. Cytokines inducing MDSCs acted on a common molecular pathway. Immunoregulatory activity of both tumor-induced and BM-derived MDSCs was entirely dependent on C/EBP transcription factor, a key component of the emergency myelopoiesis triggered by stress and inflammation. Adoptive transfer of tumor antigen-specific CD8+ T lymphocytes resulted in therapy of established tumors only in mice lacking C/EBP in myeloid compartment. These data unveil another link between inflammation and cancer and identify a novel molecular target to control tumor-induced immune suppression. We used gene expression analysis to identify those factors, secreted by tumor-infiltrating MDSC, which could drive emathopoiesis. Moreover we compare gene expression profile of tumor-induced MDSC, obtained from either the spleen and the tumor infiltrate of tumor bearing mice, and in vitro bone marrow-derived MDSC. CD11b+ cells were immunomagnetically enriched from various murine tissue and experimental conditions, and cRNA samples were prepared accordingly to Expression Analysis: Technical Manual. 701021 Rev. 5. Santa Clara, CA, Affymetrix; 2004, and hybridized to the Affymetrix GeneChip MOE430 2.0 array which contains more than 45,000 probe sets, representing more than 34,000 genes. CD11b+ cells obtained from the spleen of healthy BALB/c and C57BL/6 mice were used as reference sample for tumor induced CD11b+ MDSC, enriched from either the spleen and the tumor infiltrate of tumor-bearing mice. Moreover CD11b+ cells enriched from fresh bone marrow were used as reference sample for in vitro bone marrow-differentiated MDSC, obtained with either GM-CSF+IL-6 and GM-CSF+G-CSF 4 days cytokine cocktail treatment.
2010-06-16 | E-GEOD-21927 | biostudies-arrayexpress
Project description:Myeloid derived suppressor cells (MDSC) playing the immune suppressive roles in tumor bearing host consists of two major subsets of granulocytic and monocytic cells. Granulocytic MDSC (G-MDSC) express CD11b+ Gr-1high Ly6G+ Ly6Clow and produce high level of reactive oxygen species (ROS). Interestingly, neutrophils are well known ROS producing cells during immune defensive process and share same surface markers with G-MDSC. These similar features always brought the fundamental questions what’s the difference between G-MDSC and neutrophils but it’s not yet proven clearly. In this study, we examined the gene expression of G-MDSC and neutrophils using Affymetrix microarray
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Project description:Myeloid-derived suppressor cells (MDSC) include immature monocytic (M-MDSC) and granulocytic (PMN-MDSC) cells that share the ability to suppress adaptive immunity and hinder the effectiveness of anti-cancer treatments. Of note, in response to interferon-γ (IFNγ) M-MDSC release the tumor-promoting and immunosuppressive molecule nitric oxide (NO), whereas macrophages largely express anti-tumor properties. Investigating these opposing activities, we found that tumor-derived prostaglandin E2 (PGE2) induces nuclear accumulation of p50 NF-κB in M-MDSC, diverting their response to IFNγ towards NO-mediated immunosuppression and reducing TNFα expression. At the genome level, p50 NF-κB promoted binding of STAT1 to regulatory regions of selected IFNγ-dependent genes, including inducible nitric oxide synthase (Nos2). In agreement, ablation of p50 as well as pharmacological inhibition of either the PGE2 receptor EP2 or NO production reprogrammed M-MDSC towards a NOS2low/TNFαhigh phenotype, restoring the in vivo antitumor activity of IFNγ. Our results indicate that inhibition of the PGE2/p50/NO axis prevents MDSC suppressive functions and restores the efficacy of anticancer immunotherapy.
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Project description:Numerous case studies have reported spontaneous regression of metastases following tumor excision, but underlying mechanisms are elusive. Here we present a model of metastases regression and latency elicited by the removal of a primary tumor, and identify underlying mechanisms. Human breast cancer cells, expressing highly sensitive luciferase, were implanted into the mammary fat-pad of mice, and the progression of early stage micrometastases, was monitored. Upon establishment of micrometastases, the primary tumor was excised, inducing a robust regression of metastatic signal, resulting in latent foci. In vivo supplementation of tumor secretome immediately upon tumor excision diminished this regression, implicating primary tumor secreted factors in promotion of metastatic growth. In vitro, cancer cell conditioned medium reduced apoptosis and enhanced adhesion of non-confluent cancer cells, and induced angiogenesis in endothelial cells. Cytokine array and proteomic analysis of cancer cells secretome identified 359 extracellular secreted factors, with significant enrichment of angiogenic factors, growth factors activity, focal adhesion, apoptosis, and metalloprotease processes. In vivo blockade of four key potential mediators of these processes, IL-8, PDGFaa, Serpin E1 (PAI-1), and MIF, arrested development of micrometastases. Moreover, high protein levels of these four factors were correlated with poor patient outcome. These results demonstrate regression and latency of metastases following tumor excision and a crucial role for primary tumor secretome in promoting early metastatic stages, suggesting novel mechanisms to control minimal residual disease.
2020-10-07 | PXD008384 | Pride
Project description:CD11b+ myeloid-derived suppressor cells (MDSCs) have been shown to become activated at the tumor site and acquired a more suppressive phenotype compared to the splenic counterpart. This activated status promotes cancer progression by creating an immune suppressive niche around the tumor, by providing nourishment to the neoplastic cells, and by promoting metastases. To start understanding the differences between splenic and tumor infiltrating CD11b, genome-wide transcriptome analysis was performed. We used gene expression analysis to identify those factors, secreted by tumor-infiltrating MDSC, which could drive emathopoiesis. Moreover, we compare gene expression profile of tumor-induced MDSC, obtained from either the spleen or the tumor infiltrate of tumor-bearing mice.
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