Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Inactivation of interferon signaling promotes the establishment of an immunosuppressive microenvironment in colorectal cancers

ABSTRACT: Tumors arise and grow despite anti-cancer immune responses. These responses can be stimulated by immunotherapies such as immune checkpoint inhibitors (e.g. anti-PD1 antibodies) and chimeric antigen receptors (CAR). Efficacy of these agents in solid tumors including colorectal cancers (CRC) is limited by immunosuppressive tumor microenvironment (TME) that prevents killing of malignant cells by cytotoxic T lymphocytes (CTL). Understanding the nature of TME-generated immunosuppression is of paramount importance. Here we report that TME elicited immunosuppression via eliminating activated CTL; this elimination required TME stress-induced downregulation of the IFNAR1 chain of type I interferon (IFN) receptor and attenuation of its signaling. Downregulation of IFNAR1 was observed in human colorectal cancers (CRC) and in mouse CRC models where it was required for efficient tumor development and progression. Stabilization of IFNAR1 on CTL improved their survival and increased anti- tumor activities of CAR T cells and PD1 inhibitors thereby providing a rationale for targeting IFNAR1 degradation for immunotherapies optimization.

ORGANISM(S): Mus musculus

PROVIDER: GSE76889 | GEO | 2016/01/15

SECONDARY ACCESSION(S): PRJNA308858

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Inactivation of interferon signaling promotes the establishment of an immunosuppressive microenvironment in colorectal cancers

Project description:Tumors arise and grow despite anti-cancer immune responses. These responses can be stimulated by immunotherapies such as immune checkpoint inhibitors (e.g. anti-PD1 antibodies) and chimeric antigen receptors (CAR). Efficacy of these agents in solid tumors including colorectal cancers (CRC) is limited by immunosuppressive tumor microenvironment (TME) that prevents killing of malignant cells by cytotoxic T lymphocytes (CTL). Understanding the nature of TME-generated immunosuppression is of paramount importance. Here we report that TME elicited immunosuppression via eliminating activated CTL; this elimination required TME stress-induced downregulation of the IFNAR1 chain of type I interferon (IFN) receptor and attenuation of its signaling. Downregulation of IFNAR1 was observed in human colorectal cancers (CRC) and in mouse CRC models where it was required for efficient tumor development and progression. Stabilization of IFNAR1 on CTL improved their survival and increased anti- tumor activities of CAR T cells and PD1 inhibitors thereby providing a rationale for targeting IFNAR1 degradation for immunotherapies optimization. Two genotypes of mice were examined either 9 or 21 days post injection of MC38 colon cancer cells or MC38mRFP cells, respectively. 2-3 replicate mice were analyzed on separate arrays for each condition. 6 conditions in total were analyzed.

2016-01-15 | E-GEOD-76889 | biostudies-arrayexpress

Proteomic analysis of HepG2 cells after mutated ß-catenin depletion

Project description:ß-catenin is a main oncogene in a large number of cancers (colorectal, liver, melanoma, uterus). Local immunosuppression induced by certain cancers remains a major problem of resistance to immunotherapies and its molecular mechanism remains poorly understood. Recently, ß-catenin mutated tumors (hepatocellular carcinoma (HCC) and melanoma) have been described as promoting immune evasion and resistance to anti-PD1 immunotherapy. Based on preliminary data obtained in HCC, we hypothesize that a defect in intercellular communication could be the cause of this immune evasion. The main objective of this project is to identify proteomic signatures of factors that can induce this immune escape in ß-catenin mutated HCC such as exosomes.

2024-07-08 | PXD043841 | Pride

Targeting stromal cell sialylation reverses T cell mediated immunosuppression in the tumor microenvironment

Project description:Immunosuppressive tumor microenvironments (TME) reduce the effectiveness of immune responses in cancer. Mesenchymal stromal cells (MSC), precursors to cancer-associated fibroblasts (CAFs), dictate tumor progression by enhancing immune cell suppression in colorectal cancer (CRC). Hyper-sialylation of glycans promotes immune evasion in cancer through binding of sialic acids to their receptors, Siglecs, expressed on immune cells that results in inhibition of effector functions. The role of sialylation in dictating MSC/CAF immunosuppression in the TME is unknown. In this study, we show that tumor-conditioned stromal cells have increased sialyltransferase expression, α2,3/6-linked sialic acid and Siglec ligands. Tumor-conditioned stromal cells and CAFs induce exhausted immunomodulatory PD-1, Siglec-7 and Siglec-9-expressing T cell phenotypes. In vivo, targeting stromal cell sialylation reverses stromal cell-mediated immunosuppression, as evidenced by infiltration of CD25 and granzyme B-expressing T cells in the tumor and draining lymph node. Targeting stromal cell sialylation may overcome immunosuppression in the CRC TME.

2023-05-22 | GSE229054 | GEO

Single-cell transcriptomics analysis of the tumor microenvironment from murine MC38 xenografts upon SHP099 treatment

Project description:Colorectal cancer (CRC), a malignant tumor worldwide consists of microsatellite instability (MSI) and microsatellite stable (MSS) phenotypes. Although SHP2 is a potential target for cancer therapy, its relationship with innate immunosuppression remains elusive. To address that, single-cell RNA sequencing was performed to explore the role of SHP2 in all cell types of tumor microenvironment (TME) from murine MC38 xenografts.

2022-01-01 | GSE164908 | GEO

Inhibition of PARP11 inactivates tumor-infiltrating regulatory T cells and improves the efficacy of immunotherapies.

Project description:Tumor-infiltrating regulatory T cells (TI-Tregs) elicit immunosuppressive effects in the tumor microenviroment (TME) leading to accelerated tumor growth and resistance to immunotherapies against solid tumors. Here we demonstrate that Poly-(ADP-ribose)-polymerase-11 (PARP11) acts as an essential regulator of TI-Tregs regulatory and protumorigenic activities. Expression of PARP11 correlated with TI-Treg infiltration and poor responses to immune checkpoint blockade (ICB) in human cancer patients. PARP11 was induced in the TI-Treg cells by tumor-derived factors including adenosine and prostaglandin E2. Knockout of PARP11 in the cells of the TME or treatment of tumor-bearing mice with selective PARP11 inhibitor ITK7 inactivated TI-Treg cells and reinvigorated anti-tumor immune responses. Accordingly, ITK7 decelerated tumor growth and significantly increased the efficacy of anti-tumor immunotherapies including ICB and adoptive transfer of CAR T cells. These results characterize PARP11 as a key driver of TI-Treg activities and a major regulator of immunosuppressive TME and argue for targeting PARP11 to augment anti-cancer immunotherapies.

2023-12-07 | GSE249299 | GEO

Eum2

Project description:The low immunogenicity of many cancer cells and the immunosuppression by various cancers and anti-cancer therapies have been an obstacle in the development of efficacious immunotherapies. Our goal was to test if TLR agonists and anti-cancer chemotherapeutic agents synergize in rendering tumor cells more immunogenic.

2014-03-01 | E-MTAB-2164 | biostudies-arrayexpress

Methylation analysis of 12 corresponding pairs of TECs and NECs isolated from human CRC patients with different prognostic TMEs

Project description:Methylation analysis of 12 corresponding pairs of tumor endothelial cells (TECs) and normal endothelial cells (NECs) isolated from human colorectal carcinoma (CRC) patients with different prognostic tumor microenvironments (TMEs: Th1-TME vs Control-TME): High and low GBP-1 expression in the tumors detected by IHC was used to categorize the patient-derived cells into Th1-TME and Control-TME (compare Naschberger et al, J Clin Invest 2016 and Naschberger et al, Int J Cancer 2008). Isolation of the samples was done according to Naschberger et al, JoVE 2018. The analysis is paralleled by omics-analysis of the same cell cultures at the transcriptome (E-MTAB-10465) and genome level (E-MEXP-3993).

2023-05-01 | E-MTAB-10467 | biostudies-arrayexpress

Novel prognostic implications of complement activation in the tumor microenvironment for de novo metastatic BRAF V600E mutant colorectal cancer

Project description:Prognosis of metastatic BRAF V600E mutant colorectal cancer (CRC) is poor, and the prognostic implications of immune contextures in the tumor microenvironment (TME) for CRC remain elusive. Complement activation in the TME was significantly associated with poor OS and was correlated with TAM M2 in patients with de novo metastatic BRAF V600E mutant CRC.

2022-11-08 | GSE211576 | GEO

Immunogenetic metabolomics revealed key enzymes that modulate CAR-T metabolism and function [DNA-edit]

Project description:Immune evasion is a critical step of cancer progression that remains a major obstacle for current T cell-based immunotherapies. Hence, we seek to genetically reprogram T cells to exploit a common tumor-intrinsic evasion mechanism, whereby cancer cells suppress T cell function by generating a metabolically unfavorable tumor microenvironment (TME). Specifically, we use an in silico screen to identify ADA and PDK1 as metabolic regulators, in which gene overexpression (OE) enhances the cytolysis of CD19-specific CD8 CAR-T cells against cognate leukemia cells, and conversely, ADA or PDK1 deficiency dampens such effect. Additionally, ADA-OE in CAR-T cells improves cancer cytolysis under high concentrations of adenosine, the ADA substrate and an immunosuppressive metabolite in the TME. High-throughput transcriptomics and metabolomics in these CAR-Ts reveal alterations of global gene expression and metabolic signatures in both ADA- and PDK1- engineered CAR-T cells. Functional and immunological analyses demonstrate that ADA-OE increases proliferation and decreases exhaustion in α-CD19 and α-HER2 CAR-T cells. We then show ADA-OE improves tumor infiltration and clearance by α-HER2 CD4 and CD8 CAR-T with an in vivo colorectal cancer model. Collectively, these data unveil systematic knowledge of metabolic reprogramming directly in CAR-T cells, and reveal potential targets for improving CAR-T based cell therapy.

2023-05-18 | GSE225185 | GEO

Immunogenetic metabolomics revealed key enzymes that modulate CAR-T metabolism and function [RNA-seq]

2023-05-18 | GSE225184 | GEO