Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Combination immunotherapy can rescue CD8+ T cell dysfunction and maintain memory phenotype in cancer

ABSTRACT: In this study we unveiled specific molecular and cellular mechanisms driving the potent synergism of a coinhibitory antagonist (anti-PD-1 Ab) and a costimulatory agonist (anti-GITR Ab), a modality currently in early clinical testing, and elucidated the parameters required for durable anti-tumor responses.

ORGANISM(S): Mus musculus

PROVIDER: GSE120909 | GEO | 2018/11/02

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

RNA-seq analysis of mouse esophageal tissue following GITR agonism in a model of esophageal squamous cell cancer

Project description:Immune checkpoint modulation is an emerging therapeutic strategy for the treatment of esophageal squamous cell cancer (ESCC), but current strategies only benefit a fraction of patients. Glucocorticoid-induced TNFR-related protein (GITR) is a costimulatory immune checkpoint molecule that, upon engagement, can induce anti-tumor activity in solid tumor models. Here, we performed RNA sequencing analysis following targeting of GITR with an agonist antibody (clone DTA-1) or isotype control in the 4-nitroquinoline-1-oxide (4-NQO) mouse model of ESCC.

2022-11-01 | GSE202545 | GEO

Gene expression based outcome of CT-26 tumor in C57/BL6 mice after treatment with anti-PD-1 antibody, GITR-L, combination or Bispecific molecules

Project description:Co-stimulatory receptors such as GITR play key roles in regulating the effector functions of T cells. Agonistic anti-GITR antibodies have been investigated as a cancer immunotherapy with demonstrated efficacy in pre-clinical models. In human clinical trials, however, GITR agonist antibodies have shown limited therapeutic effect which may be due to a suboptimal receptor clustering-mediated signaling. To overcome this potential limitation, a rational protein engineering approach is needed to optimize GITR agonist-based immunotherapies. Here we show a novel bispecific molecule consisting of an anti-PD-1 antibody fused with a multimeric GITR ligand (anti-PD-1-GITR-L) that induces a PD-1-dependent and FcγR-independent GITR clustering, resulting in an enhanced activation, proliferation, and memory differentiation of primed antigen-specific GITR+PD-1+ T cells. The anti-PD-1-GITR-L bispecific is a PD-1 directed GITR-L construct that has a different mechanism of action (MoA) than the co-administration of anti-PD-1 plus GITR-L and demonstrated a dose-dependent immunologically driven tumor growth inhibition in syngeneic, genetically engineered and xenograft humanized mouse tumor models. Combination of anti-PD-1-GITR-L with TGFβ inhibition or chemotherapy (gemcitabine), respectively, resulted in tumor remission in immunogenically cold and checkpoint blockade resistant mouse models. Dose-dependent correlations between target saturation and Ki67 and TIGIT up-regulation on memory T cells have been observed following a single dose of anti-PD-1-GITR-L bispecific in mice and non-human primates. Anti-PD-1-GITR-L thus represents a novel bispecific approach for directing GITR agonism for cancer immunotherapy.

2021-12-20 | GSE189359 | GEO

Single cell transcriptome and surface protein expression analysis identify OX40+GITR+ pathogenic T helper 17 in anklyosing spondilytis [CITE-seq]

Project description:We unveiled the characteristics of pTh17s, which are polyfunctional IL-17A and IFN-γ-producing memory CD4+ T cells. scRNA-seq and cytometry analysis found that the co-expression of OX40 and GITR is increased in pTh17 cells.

2023-02-23 | GSE216884 | GEO

Single cell transcriptome and surface protein expression analysis identify OX40+GITR+ pathogenic T helper 17 in anklyosing spondilytis [scRNA-seq]

2023-02-23 | GSE216883 | GEO

Therapy of Established Tumors with Rationally Designed Multiple Agents Targeting Diverse Immune-Tumor Interactions: Engage, Expand, Enable

Project description:Immunotherapy of immunologically cold solid tumors may require multiple agents to (a) engage immune effector cells, (b) expand effector populations and activities, and (c) enable immune response in the tumor microenvironment (TME). To target these distinct phenomena, we strategically chose five clinical-stage immuno-oncology agents, namely, (a) a tumor antigen-targeting adenovirus-based vaccine (Ad-CEA) and an IL-15 superagonist (N-803) to activate tumor specific T cells, (b) OX40 and GITR agonists to expand and enhance the activated effector populations, and (c) an IDO inhibitor (IDOi) to enable effector cell activity in the TME. Flow cytometry, TCR sequencing, and RNAseq analyses showed that in the CEA-transgenic murine colon carcinoma (MC38-CEA) tumor model, Ad-CEA + N-803 combination therapy resulted in immune-mediated anti-tumor effects and promoted the expression of costimulatory molecules on immune subsets, OX40 and GITR, and the inhibitory molecule IDO. Treatment with Ad-CEA + N-803 + OX40 + GITR + IDOi, termed the pentatherapy regimen, resulted in the greatest inhibition of tumor growth and protection from tumor rechallenge without toxicity. Monotherapy with any of the agents had little to no anti-tumor activity, while combining two, three, or four agents had minimal anti-tumor effects. Immune analyses demonstrated that the pentatherapy combination induced CD4+ and CD8+ T cell activity in the periphery and tumor and anti-tumor activity associated with decreased Treg immunosuppression in the TME. The pentatherapy combination also inhibited tumor growth and metastatic formation in 4T1 and LL2-CEA murine tumor models. Significance: This study provides the rationale for the combination of multi-modal immunotherapy agents to engage, enhance, and enable adaptive anti-tumor immunity.

2021-02-10 | GSE162799 | GEO

Single-cell mRNA sequencing of anti-PD-1 GITR-L bispecific antibody treated CT26 mouse tumor model infiltrating leukocytes

Project description:Single-cell mRNA sequencing of anti-PD-1 GITR-L bispecific antibody treated CT26 mouse tumor model infiltrating leukocytes

2021-12-20 | GSE190105 | GEO

Expression data of alloantigen stimulated splenocytes treated with leukocyte costimulatory blockade antibodies or no treatment

Project description:To elucidate the gene expression “footprint” of antigenically challenged T-cells which had been treated with anti-LFA-1, CTLA4Ig, anti-CD40-ligand antibodies, we performed microarray gene expression analysis comparing the expression profile of costimulatory blockade treated and untreated responder T-cells. Allogeneic murine splenocytes were co-cultured in an vitro set-up for a mixed lymphocyte reaction. For the experimental/treated group, the leuckocyte costimulatory blocking antibodies anti-LFA-1, CTLA4Ig, anti-CD40-ligand were added to the media, the control group did not have any antiodies added to the media. After 5 days of incubation the responder CD4 and CD8 T cells were isolated by FACS and the gene expression was analyzed using affymetrix microarray platforms.

2011-02-03 | E-GEOD-26669 | biostudies-arrayexpress

GITR and GITRL protects non-epithelioid mesothelioma cells from radiation

Project description:GITR and GITRL overexpress in sarcomatoid mesotelioma cells than epithelioid subtype, and cisplatin or radiation results an increase of GITR and GITRL expression on tumor cells. After sorting CRL9546 cells into GITR+(R), GITRL+(L), and GITR-/GITRL- (DN) cell populations. Three cell subsets were labelled as ligand positive L1, L2, L3, receptor positive R1, R2, R3, and double negative DN1, DN2, DN3. In total: 9 samples. RNA was extracted to run Affymetrix microarray.

2021-11-02 | E-MTAB-10647 | biostudies-arrayexpress

Genome-wide maps of Runx3 bound regions in splenic NK cells

Project description:ChIP-seq was conducted using freshly isolated (resting) splenic WT NK cells with anti-Runx3 antibody (Ab), anti-H3K4me1 Ab and non-immune serum (NIS) as control.

2013-11-18 | GSE50127 | GEO

Genome-wide maps of Runx3 bound regions in splenic CD8+ T cells.

Project description:ChIP-seq was conducted using freshly isolated (resting) splenic WT CD8+ T cells with anti-Runx3 antibody (Ab), anti-H3K4me1 Ab and non-immune serum (NIS) as control.

2013-11-18 | GSE50130 | 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