JAK inhibition selectively suppresses melanoma lacking IFN-γ pathway
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE201078 | GEO | 2022/07/31
REPOSITORIES: GEO
Similar Datasets
Project description:Tumors expressing high level of programmed cell death-1 (PD-1) ligand 1 (PD-L1) are more likely to respond to immune checkpoint blockers (ICBs) targeting PD-1 or PD-L1. However, more than half of tumor patients with high PD-L1 expression does not respond to ICBs and the underlying mechanisms are yet to be clarified. Here we show that depletion of developmentally regulated GTP-binding protein 2 (DRG2) inhibited recycling of endosomal PD-L1 and reduced surface PD-L1 level in melanoma cells. DRG2-depleted cells showed decreased binding with recombinant PD-1. Although DRG2-depleted cells expressed high levels of PD-L1, anti-PD-1 ICB did not activate T cells within DRG2-depleted tumors and failed to improve the survival of DRG2-depleted tumor-bearing mice. Cohort analysis of melanoma patients under anti-PD-1 treatment revealed that patients bearing tumors with high DRG2 protein level were more sensitive to PD-1 anti-PD-1 ICBs. These findings identify DRG2 as a regulator of recycling of endosomal PD-L1 and a key determinant for response to anti-PD-1 ICB and provide insights into how to increase the correlation between PD-L1 expression and response to ICB.
2023-11-06 | GSE231973 | GEO
Project description:Tumors expressing high level of programmed cell death-1 (PD-1) ligand 1 (PD-L1) are more likely to respond to immune checkpoint blockers (ICBs) targeting PD-1 or PD-L1. However, more than half of tumor patients with high PD-L1 expression does not respond to ICBs and the underlying mechanisms are yet to be clarified. Here we show that depletion of developmentally regulated GTP-binding protein 2 (DRG2) inhibited recycling of endosomal PD-L1 and reduced surface PD-L1 level in melanoma cells. DRG2-depleted cells showed decreased binding with recombinant PD-1. Although DRG2-depleted cells expressed high levels of PD-L1, anti-PD-1 ICB did not activate T cells within DRG2-depleted tumors and failed to improve the survival of DRG2-depleted tumor-bearing mice. Cohort analysis of melanoma patients under anti-PD-1 treatment revealed that patients bearing tumors with high DRG2 protein level were more sensitive to PD-1 anti-PD-1 ICBs. These findings identify DRG2 as a regulator of recycling of endosomal PD-L1 and a key determinant for response to anti-PD-1 ICB and provide insights into how to increase the correlation between PD-L1 expression and response to ICB.
2023-11-06 | GSE231972 | GEO
Project description:The combination of PD-1 and CTLA-4 blockade has determined an improved overall survival (OS) rate for malignant melanoma at 3 years of 58% as compared to ipilimumab alone. Immune checkpoint blockers (ICB) limit the tumor’s immune escape yet only for approximately a third of all tumors and, in most cases, for a limited amount of time. Several approaches to overcome resistance to ICB are being investigated among which the addition of epigenetic drugs that are expected to act on both immune and tumor cells. Guadecitabine, a dinucleotide prodrug of a decitabine linked via phosphodiester bond to a guanosine, showed promising results in the phase-1 clinical trial, NIBIT-M4 (NCT02608437). We used the syngeneic B16F10 murine melanoma model to study the effects of immune checkpoint blocking antibodies against CTLA-4 and PD-1 in combination, with and without the addition of Guadecitabine. We comprehensively characterized the tumor’s and the host’s responses under different treatments by flow cytometry, immunohistochemistry (MANTRA), gene methylation and scRNA sequencing. Guadecitabine in combination with ICBs significantly reduced tumor growth compared to ICB and Guadecitabine treatment. The demethylating drug led to a general DNA-demethylation and transcriptional modification of gene expression. In particular, Guadecitabine greatly enhanced the efficacy of combined ICBs by increasing effector memory CD8+ T cells, inducing effector NK cells in the spleen and reducing tumor infiltrating regulatory T cells and MDSC cells, in the TME. These results indicate Guadecitabine as a promising epigenetic drug to be added to ICB therapy.
2023-04-25 | GSE220698 | GEO
Project description:Immune checkpoint blockers (ICBs) have failed in all Phase III glioblastoma trials. Here, we found that ICBs induce cerebral edema in some patients and mice with glioblastoma. Through single-cell RNA sequencing, intravital imaging, and T cell blocking studies in mice, we demonstrated that this edema results from an inflammatory response following anti-PD1 antibody treatment that disrupts the blood-tumor-barrier. Used in lieu of immunosuppressive corticosteroids, the angiotensin receptor blocker losartan prevented this ICB-induced edema and reprogrammed the tumor microenvironment, curing 20% of mice which increased to 40% in combination with standard of care treatment. Using a bihemispheric tumor model, we identified a “hot” tumor immune signature prior to losartan+anti-PD1 therapy that predicted long-term survival. Our findings provide the rationale and associated biomarkers to test losartan with ICBs in glioblastoma patients.
2023-01-01 | GSE212246 | GEO
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
Project description:The idea that stem cell therapies work only via cell replacement is challenged by the observation of consistent intercellular molecule exchange between the graft and the host. Here we defined a mechanism of cellular signaling by which neural stem/precursor cells (NPCs) communicate with the microenvironment via extracellular vesicles (EVs), and we elucidated its molecular signature and function. We observed cytokine-regulated pathways that sort proteins and mRNAs into EVs. We described induction of interferon gamma (IFN-?) pathway in NPCs exposed to proinflammatory cytokines that is mirrored in EVs. We showed that IFN-? bound to EVs through Ifngr1 activates Stat1 in target cells. Finally, we demonstrated that endogenous Stat1 and Ifngr1 in target cells are indispensable to sustain the activation of Stat1 signaling by EV-associated IFN-?/Ifngr1 complexes. Our study identifies a mechanism of cellular signaling regulated by EV-associated IFN-?/Ifngr1 complexes, which grafted stem cells may use to communicate with the host immune system. polyA RNA profiling of Neural Stem/Progenitor cells (NPCs) cultured in basal/Th1/Th2 conditions, of Exosomes derived from NPCs cultured in basal/Th1/Th2 conditions and of EVs derived from NPCs cultured in Basal/Th1/Th2 conditions. Total RNA was purified using Trizol. Purity and integrity were confirmed by BioAnalyser (Agilent). Paired End library construction and poly-A selection were performed by EASIH (The Eastern Sequence and Informatics Hub, University of Cambridge, Cambridge) according to the Illumina standard protocol. Sequencing was performed by EASIH using Illumina GAII.
2014-09-22 | E-GEOD-33527 | biostudies-arrayexpress
Project description:<p>Although immune checkpoint blockade (CPB) leads to prolonged responses in 15-40% of patients with metastatic melanoma, treatment refractory disease and progression after initial response remain major causes of mortality. While predictors of response have been reported, the common mechanisms of both primary and acquired resistance are poorly understood. To identify mechanisms of resistance and examine the evolving landscape in response to CPB, we performed whole exome sequencing (WES), immunohistochemistry (IHC), and RNA-sequencing (RNAseq) of longitudinal tumor biopsies from 17 metastatic melanoma patients treated with various CPB therapies. We found no significant changes in both mutational and neoantigen loads over time between responders and nonresponders. However, we identified abnormalities in one gene, beta-2-microglobulin (<i>B2M</i>), an essential component of MHC Class I antigen presentation, that were present in samples during disease progression but not regression. In total, we identified <i>B2M</i> aberrations in 29.4% of patients, including multiple early frameshift mutations, loss of heterozygosity (LOH) overlapping <i>B2M</i>, and absence of tumor-specific <i>B2M</i> protein expression. Additional defects in the antigen presentation and IFNγ pathways were identified but were not restricted to progressing lesions in our cohort. In two independent cohorts of 105 and 38 melanoma patients treated with ipilimumab (anti-CTLA4) and pembrolizumab (anti-PD1) respectively, we found that <i>B2M</i> LOH was enriched 3-fold in nonresponders (~30%) vs. responders (~10%) and associated with poorer overall survival (log-rank p=0.01, p=0.006). Loss of both copies of <i>B2M</i> was found only in nonresponders. We also found evidence for association of LOH overlapping <i>IFNGR1</i> with poorer overall survival exclusively in the anti-PD1 cohort. Thus, <i>B2M</i> loss is likely a common mechanism of primary and acquired resistance to therapies targeting CTLA4 or PD-1.</p>
| phs001427 | dbGaP
Project description:The idea that stem cell therapies work only via cell replacement is challenged by the observation of consistent intercellular molecule exchange between the graft and the host. Here we defined a mechanism of cellular signaling by which neural stem/precursor cells (NPCs) communicate with the microenvironment via extracellular vesicles (EVs), and we elucidated its molecular signature and function. We observed cytokine-regulated pathways that sort proteins and mRNAs into EVs. We described induction of interferon gamma (IFN-γ) pathway in NPCs exposed to proinflammatory cytokines that is mirrored in EVs. We showed that IFN-γ bound to EVs through Ifngr1 activates Stat1 in target cells. Finally, we demonstrated that endogenous Stat1 and Ifngr1 in target cells are indispensable to sustain the activation of Stat1 signaling by EV-associated IFN-γ/Ifngr1 complexes. Our study identifies a mechanism of cellular signaling regulated by EV-associated IFN-γ/Ifngr1 complexes, which grafted stem cells may use to communicate with the host immune system.
2014-09-22 | GSE33527 | GEO
Project description:The role of HIF1a-glycolysis in regulating IFN-g induction in hypoxic T cells is unknown. Given that hypoxia is a common feature in a wide array of pathophysiological contexts such as tumor and that IFN-g is instrumental for protective immunity, it is of great significance to gain a clear idea on this. Combining pharmacological and genetic gain-of-function and loss-of-function approaches, we find that HIF1a-glycolysis controls IFN-g induction in both human and mouse T cells activated under hypoxia. Specific deletion of HIF1a in T cells (HIF1a–/–) and glycolytic inhibition significantly abrogate IFN-g induction. Conversely, HIF1a stabilization in T cells by hypoxia and VHL deletion (VHL–/–) promotes IFN-g production. Mechanistically, reduced IFN-g production in hypoxic HIF1a–/– T cells is due to attenuated activation-induced cell death but not proliferative defect. We further show that depletion of intracellular acetyl-CoA is a key metabolic underlying mechanism. Hypoxic HIF1a–/– T cells are less able to kill tumor cells, and HIF1a–/– tumor-bearing mice are not responsive to immune checkpoint blockade (ICB) therapy, indicating loss of HIF1a in T cells is a major mechanism of therapeutic resistance to ICBs. Importantly, acetate supplementation restores IFN-g production in hypoxic HIF1a–/– T cells and re-sensitizes HIF1a–/– tumor-bearing mice to ICBs, providing an effective strategy to overcome ICB resistance. Taken together, our results highlight T cell HIF1a-anaerobic glycolysis as a principal mediator of IFN-g induction and anti-tumor immunity. Considering that acetate supplementation (i.e., glycerol triacetate (GTA)) is approved to treat infants with Canavan disease, we envision a rapid translation of our findings, justifying further testing of GTA as a repurposed medicine for ICB resistance, a pressing unmet medical need
2024-09-24 | GSE253090 | GEO
Project description:JAK inhibition selectively suppresses melanoma lacking IFN-γ pathway
| PRJNA828250 | ENA