Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Loss of tumor suppressors promotes a non-cell-autonomous inflammatory tumor microenvironment and enhances LAG3+T cell mediated immune suppression [RNA_seq_vitro]

ABSTRACT: Low response rate, treatment relapse, and resistance remain key challenges in the application of immune checkpoint blockade (ICB). Here we report that loss of specific tumor suppressors (TSs) induces an inflammatory response and promotes an immune suppressive tumor microenvironment. Importantly, low expression of these TSs is associated with a higher expression of immune checkpoint inhibitory mediators. Using CRIPSR/Cas9 in vivo loss-of-function screening, we identified NF1, TSC1, and TGF-b RII as TSs that regulate immune composition. Loss of each of these three TSs leads to alterations in chromatin accessibility and enhances IL6-JAK3-STAT3/6 inflammatory pathways. This results in an immune suppressive landscape characterized by increased LAG3+ CD8 and CD4 T cells. ICB targeting LAG3 in combination with PD-L1 decreased metastatic progression in preclinical triple negative breast cancer (TNBC) mouse models of NF1-, TSC1- or TGF-b RII- deficient tumors. Together, our studies identify LAG3 as a new ICB target for patients whose cancer displays inactivation of these TSs. In addition, our studies reveal an unexpected role for TSs in the regulation of metastatic spread via non-cell-autonomous modulation of the immune compartment.

ORGANISM(S): Mus musculus

PROVIDER: GSE249971 | GEO | 2024/03/01

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Loss of tumor suppressors promotes a non-cell-autonomous inflammatory tumor microenvironment and enhances LAG3+T cell mediated immune suppression [RNA_seq_Cas9_PT]

Project description:Low response rate, treatment relapse, and resistance remain key challenges in the application of immune checkpoint blockade (ICB). Here we report that loss of specific tumor suppressors (TSs) induces an inflammatory response and promotes an immune suppressive tumor microenvironment. Importantly, low expression of these TSs is associated with a higher expression of immune checkpoint inhibitory mediators. Using CRIPSR/Cas9 in vivo loss-of-function screening, we identified NF1, TSC1, and TGF-b RII as TSs that regulate immune composition. Loss of each of these three TSs leads to alterations in chromatin accessibility and enhances IL6-JAK3-STAT3/6 inflammatory pathways. This results in an immune suppressive landscape characterized by increased LAG3+ CD8 and CD4 T cells. ICB targeting LAG3 in combination with PD-L1 decreased metastatic progression in preclinical triple negative breast cancer (TNBC) mouse models of NF1-, TSC1- or TGF-b RII- deficient tumors. Together, our studies identify LAG3 as a new ICB target for patients whose cancer displays inactivation of these TSs. In addition, our studies reveal an unexpected role for TSs in the regulation of metastatic spread via non-cell-autonomous modulation of the immune compartment.

2024-03-01 | GSE249969 | GEO

Loss of tumor suppressors promotes a non-cell-autonomous inflammatory tumor microenvironment and enhances LAG3+T cell mediated immune suppression [ATAC_seq]

2024-03-01 | GSE249967 | GEO

Immunologic and clinical activity to ICB combinations in DAPPER Leiomyosarcoma cohort

Project description:Non-inflamed (cold) tumors such as leiomyosarcoma (LMS) do not benefit from immune checkpoint blockade (ICB) monotherapy. Combining ICB with angiogenesis-, or poly-ADP ribose polymerase (PARP) inhibitors may increase tumor immunogenicity by altering the immune cell composition of the tumor microenvironment (TME). The DAPPER phase II study evaluated the safety, immunologic, and clinical activity of ICB-based combinations in pre-treated LMS patients.

2024-01-01 | E-MTAB-12922 | biostudies-arrayexpress

Role of intratumoral CD11b+ cells in immune checkpoint resistance in GBM

Project description:Glioblastomas show low response rates to immune checkpoint blockade with few hypermutated glioblastomas showing responses. Moreover, a growing body of evidence suggests that macrophages in the glioblastoma microenvironment impair anti-tumor immunity and immunotherapy approaches. Here, we investigate macrophage-mediated mechanisms of response and resistance to combinatory immune checkpoint blockade targeting PD-1 and CTLA-4 in the murine syngeneic Gl261 glioblastoma model. Nanostring analysis from CD45highCD11b+ cells isolated from ICB responder and non-responder Gl261 tumors was performed. Here, we provide evidence for a differential expression of pro- and anti-inflammatory genes in CD45highCD11b+ cells from ICB responder and non-responder tumors pointing towards a suppressive phenotype of ICB non-responder CD45highCD11b+ cells. Targeting these suppressive CD45highCD11b+ cells in the glioblastoma microvenvironment might thus potentiate ICB efficacy.

2020-02-03 | GSE129877 | GEO

Systemic LRG1 expression in melanoma is associated with disease progression and recurrence

Project description:Treatment of late-stage melanoma patients with immune checkpoint blockade (ICB) is currently one of the most effective standard therapies. The response rates upon neoadjuvant ICB in stage III melanoma are higher as compared to stage IV disease. Given that successful ICB depends on systemic immune response, we hypothesized that systemic immune suppression might be a mechanism responsible for lower response rates in late-stage disease, and also potentially with disease recurrence in early-stage disease.

2024-01-09 | PXD040399 | Pride

IL-27 stimulation in Foxp3+ Tregs improves suppressive function and therapeutic efficacy

Project description:Foxp3 expressing regulatory T cells (Tregs) are the central regulator of immune homeostasis and tolerance. As it is believed that proper Treg function is compromised under inflammatory conditions, exploring a pathway that enhances Treg function is of great importance. In this study, we report that IL-27, an IL-12 family cytokine known to play both pro- and anti-inflammatory role in T cells, plays a pivotal role in Treg function to control T cell-induced colitis. Unlike WT Tregs capable of inhibiting colitogenic T cell expansion and inflammatory cytokine expression, IL-27R-deficient Tregs were unable to downregulate inflammatory T cell responses. Tregs stimulated with IL-27 expressed substantially enhanced suppressive function both in vitro and in vivo. IL-27 stimulation of Tregs induced expression of LAG3, a surface molecule implicated in negatively regulating immune responses. LAG3 expression in IL-27-stimulated Tregs was critical to mediate suppressive Treg function. Finally, human Tregs also displayed enhanced suppressive function and LAG3 expression in response to IL-27 stimulation. Taken together, our results highlight a novel function of the IL-27/LAG3 axis in Treg regulation of inflammatory responses in the intestine. FACS purified Foxp3+ Tregs were stimulated in the presence of media or IL-27 to compare IL-27 induced gene profiles. Four samples (media stimulated or IL-27-stimulated) were collected from four independent experiments. Genes altered by IL-27 treatment were compared to those of media stimulated Tregs.

2015-11-01 | E-GEOD-63455 | biostudies-arrayexpress

Tsc1 promotes the differentiation of memory CD8+ T cells via orchestrating the transcriptional and metabolic programs

Project description:Memory CD8+ T cells are an essential component of protective immunity. Signaling via mechanistic target of rapamycin (mTOR) has been implicated in the regulation of the differentiation of effector and memory T cells. However, little is understood about the mechanisms that control mTOR activity, or the effector pathways regulated by mTOR, in this process. We describe here that tuberous sclerosis 1 (Tsc1), a regulator of mTOR signaling, plays a crucial role in promoting the differentiation and function of memory CD8+ T cells in response to Listeria monocytogenes infection. Mice with specific deletion of Tsc1 in antigen-experienced CD8+ T cells evoked normal effector responses, but were markedly impaired in the generation of memory T cells and their recall responses to antigen re-exposure in a cell-intrinsic manner. Tsc1 deficiency suppressed the generation of memory-precursor effector cells (MPECs) while promoting short-lived effector cell (SLEC) differentiation. Functional genomic analysis indicated that Tsc1 coordinated gene expression programs underlying immune function, transcriptional regulation and cell metabolism. Furthermore, Tsc1 deletion led to excessive mTORC1 activity and dysregulated cellular metabolism including glycolytic and oxidative metabolism. These findings establish a Tsc1-mediated checkpoint in linking immune signaling and cell metabolism to orchestrate memory CD8+ T cell development and function. We used microarrays to explore the gene expression profiles differentially expressed in OVA-specific CD8+ T-cells from wild-type (WT; Tsc1-fl/fl and cre-negative) and Tsc1-/- (Tsc1-fl/fl and Granzyme B-cre-positive) mice

2014-09-20 | E-GEOD-61591 | biostudies-arrayexpress

Identification of potential substrates of TRABID in HeLa cells using SILAC

Project description:Immune checkpoint blockades (ICBs) have been approved for treating multiple cancer types, but the response rate is limited for many solid tumors. Much efforts have been devoted to understand the mechanisms governing ICB therapy efficacy and the abundance of tumor-infiltrating lymphocytes is among the factors that influence on ICB responsiveness. The deubiquitinase TRABID was identified in our previous study as a positive regulator of autophagy by stabilizing VPS34, the class III PI3K critical for autophagosome formation. In this study, we identify an upregulation of TRABID in mitosis and its critical role in mitotic progression through deubiquitination and stabilization of AURKB and BIRC5, two subunits of the chromosome passenger complex governing multiple mitotic steps. Furthermore, TRABID depletion induces micronuclei phenotype, which is likely mediated by the combinatory defects in mitosis and autophagy. Consequently, TRABID depletion or inhibition activates cGAS/STING pathway to induce type I interferon production and inflammatory responses. TRABID depletion in tumors cells reduces tumor burden and promotes anti-tumor immune surveillance by increasing tumor infiltration of CD4+ and CD8+ T cells and NK cells and reducing Treg cells. Clinically, TRABID expression in multiple cancer types correlates negatively with the infiltration of anti-tumor immune cells and positively with that of pro-tumor immune cells. Our study supports a suppressive role of tumor-intrinsic TRABID in anti-tumor immunity and suggests TRABID inhibitor as a promising agent for enhancing the sensitivity of solid tumors to ICB therapy.

2023-05-11 | PXD035002 | Pride

Re-education of myeloid immune cells to reduce regulatory T cell expansion and impede breast cancer progression [BMDM_RNA-Seq]

Project description:Due to the limited efficacy of Immune checkpoint blockade (ICB) in mammary solid tumors alternative strategies are required. We demonstrated that cholesterol homeostasis plays a significant role in myeloid immune function and breast cancer progression. In this study, we focus on NR0B2. We conducted both in vitro and in vivo studies along with developing a small molecule agonist. NR0B2 functions within myeloid immune cells as a regulator of the NLRP3 inflammasome, which further facilitates T cell differentiation away from immune-suppressive regulatory T cells (Treg). Furthermore, this signaling pathway was demonstrated to attenuate breast tumor growth and metastasis in mouse models.

2023-09-04 | GSE241916 | GEO

Re-education of myeloid immune cells to reduce regulatory T cell expansion and impede breast cancer progression [PyMT_RNA-Seq]

2023-09-04 | GSE241915 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data