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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE202545 | GEO | 2022/11/01

REPOSITORIES: GEO

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Cyclophosphamide enhances the anti-tumor potency of GITR engagement by increasing oligoclonal cytotoxic T cell fitness

Project description:Immune checkpoint blockade (ICB) therapy is a standard treatment option for many malignancies, but it is only effective in a subset of patients. Combination strategies to overcome resistance are promising areas of investigation. Targeting glucocorticoidinduced TNFR-related (GITR) protein with agonist antibodies has shown efficacy in preclinical models, but GITR engagement does not control growth of advanced poorly immunogenic murine tumors such as B16 melanoma and has not yielded benefit in clinical trials. The alkylating agent cyclophosphamide (CTX) preferentially depletes regulatory T cells (Tregs) and expands tumor-specific effector T cells (Teffs) via homeostatic proliferation. Additionally, CTX directly induces tumor cell death, thereby releasing antigen to prime Teffs in a lymphopenic environment where there are fewer Tregs. GITR agonism has a net inhibitory effect on Tregs and yet activates Teff. We therefore hypothesized that CTX treatment prior to GITR agonism would promote potent anti-tumor immunity. Here we show that the combination of CTX and GITR agonism robustly controls tumor growth in several clinically relevant mouse models. Mechanistically, we show that the combination therapy causes tumor cell death, clonal expansion of highly active and terminally differentiated CD8+ T cells, and depletion of regulatory T cells by AICD. Control of tumor growth was also associated with the presence of an expanded population of highly activated tumor-infiltrating oligoclonal CD8+ T cells that lead to a global contracted TCR repertoire. Our studies show that the combination of CTX and GITR agonism is a rational chemo-immunotherapeutic approach that warrants further clinical investigation.

2021-11-18 | GSE182292 | GEO

Targeting Treg cells with GITR activation alleviates resistance to immunotherapy in murine glioblastomas

Project description:Immune checkpoint blockers (ICBs) have failed in all phase III glioblastoma (GBM) trials. Here, we show that regulatory T (Treg) cells play a key role in GBM resistance to ICBs in experimental gliomas. Targeting glucocorticoid-induced TNFR-related receptor (GITR) in Treg cells using an agonistic antibody (αGITR) promotes CD4 Treg cell differentiation into CD4 effector T cells, alleviates Treg cell-mediated suppression of anti-tumor immune response, and induces potent anti-tumor effector cells in GBM. The reprogrammed GBM-infiltrating Treg cells express genes associated with a Th1 response signature, produce IFNγ, and acquire cytotoxic activity against GBM tumor cells while losing their suppressive function. αGITR and αPD1 antibodies increase survival benefit in three experimental GBM models, with a fraction of cohorts exhibiting complete tumor eradication and immune memory upon tumor re-challenge. Moreover, αGITR and αPD1 synergize with the standard of care treatment for newly-diagnosed GBM, enhancing the cure rates in these GBM models.

2021-03-27 | GSE167746 | GEO

Transcription profiling of mouse lymphoma L5178Y cells treated with 4-NitroQuinoline N-Oxide (4-NQO) ILSI-HESI Genotoxicity Study - 4-NQO

Project description:Mouse lymphoma L5178Y cells are treated with 4-NitroQuinoline N-Oxide (4-NQO) [CAS:56-57-5;CHEBI:16907] and harvested at 4 and 24 hours for analysis.

2006-02-13 | E-TOXM-1 | 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

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

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

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

| PRJNA836540 | ENA

Eosinophils exert direct and indirect anti-tumorigenic effects in the development of esophageal squamous cell carcinoma [4NQOinDBLgata]

Project description:Eosinophils are present in several solid tumors and have context-dependent function. The role of eosinophils in the development of esophageal squamous cell cancer (ESCC), 85% of esophageal cancers worldwide, is unknown. Mice were treated with 4-nitroquinolone-1-oxide (4-NQO) for 8 weeks followed by vehicle for 8 weeks to induce esophageal squamous pre-cancer. Eosinophil depletion using three mouse models resulted in exacerbated 4-NQO tumorigenesis. RNA-sequencing on the whole esophagus of WT and ?dblGATA mice was done in the pre-cancer model to understand how the presence of eosinophils affects the pre-cancer esophageal environment.

2023-12-01 | GSE233443 | GEO

Eosinophils exert direct and indirect anti-tumorigenic effects in the development of esophageal squamous cell carcinoma [eos]

Project description:Eosinophils are present in several solid tumors and have context-dependent function. The role of eosinophils in the development of esophageal squamous cell cancer (ESCC), 85% of esophageal cancers worldwide, is unknown. Mice were treated with 4-nitroquinolone-1-oxide (4-NQO) for 8 weeks followed by vehicle for 8 weeks to induce esophageal squamous pre-cancer. Eosinophil depletion using three mouse models resulted in exacerbated 4-NQO tumorigenesis. In order to study the transcriptional profiles of eosinophils specifically, we isolated eosinophils from esophageal tissue of WT mice which had been treated with 4-NQO in the pre-cancer model. Because eosinophils are not present in the esophagus normally, we isolated eosinophils from the colons of a random subset of the same mice. Additionally, we derived eosinophils from the bone marrow of a random subset of the same mice.

2023-12-01 | GSE233448 | GEO

Genome-wide changes in transcript levels in tongues after 4-NQO and ethanol treatment

Project description:Tobacco use and alcohol consumption are two major contributing factors for head and neck squamous cell carcinoma (HNSCC) carcinogenesis. We combined the 4-nitroquinoline-1-oxide (4-NQO) oral carcinogenesis mouse model and the Meadows-Cook alcohol mouse models and performed next generation genome-wide RNA-sequencing of tongues. We determined changes in transcript levels in four groups: 4-NQO followed by ethanol treatment (4-NQO/EtOH), 4-NQO followed by normal drinking water (4-NQO/Untr.), vehicle control followed by ethanol treatment (V.C./EtOH), and vehicle control followed by normal drinking water (V.C./Untr.). We found that the 494 gene transcripts were significantly changed (at least a 2-fold change where p<0.05) in the V.C./EtOH group compared to the V.C./Untr. group. The 4-NQO/Untr. group had 1,808 transcripts significantly changed compared to the V.C./Untr group, while the 4-NQO/EtOH group had 3,606 significantly changed transcripts as compared to the V.C/Untr. group. This study is the first to show that 4-NQO followed by ethanol cause the largest number of changes in transcript levels in the tongue.

2015-10-06 | GSE62125 | GEO

Toxicogenomic responses in rainbow trout hepatocytes exposed to model chemicals and a synthetic mixture

Project description:Comparison of gene expression of exposed versus non-exposed Oncorhynchus mykiss hepatocytes to four model chemicals and a synthetic mixture. Hepatocytes were exposed for 24 hours to a single chemical and a synthetic mixture of 10 nM 17 alpha-ethinylestradiol (EE2), 0.75 nM 2,3,7,8-tetrachloro-di-benzodioxin (TCDD), 100 Î¼M paraquat and 0.75 Î¼M 4-nitroquinoline-1-oxide (NQO). Four biological replicates for both exposed and non-exposed Oncorhynchus mykiss hepatocytes with corresponding dye flips.

2010-06-05 | E-GEOD-6416 | biostudies-arrayexpress

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