Activin-A impedes the establishment of CD4+ T cell exhaustion and enhances anti-tumor immunity in the lung [RNA-seq]
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ABSTRACT:
PROVIDER: PRJNA761264 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
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| SRR15734975.fastq.gz | Fastqsanger.gz | |||
| SRR15734976.fastq.gz | Fastqsanger.gz | |||
| SRR15734977.fastq.gz | Fastqsanger.gz | |||
| SRR15734978.fastq.gz | Fastqsanger.gz |
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Project description:Activin-A impedes the establishment of CD4+ T cell exhaustion and enhances anti-tumor immunity in the lung [RNA-seq]
| PRJNA761264 | ENA
Project description:Background: Although tumor-infiltrating T cells represent a favorable prognostic marker for cancer patients, the majority of these cells are rendered with an exhausted phenotype. Hence, there is an unmet need to identify factors which can reverse this dysfunctional profile and restore their anti-tumorigenic potential. Activin-A is a pleiotropic cytokine, exerting a broad range of pro- or anti-inflammatory functions in different disease contexts, including allergic and autoimmune disorders and cancer. Given that activin-A exhibits a profound effect on CD4+ T cells in the airways and is elevated in lung cancer patients, we hypothesized that activin-A can effectively regulate anti-tumor immunity in lung cancer. Methods: To evaluate the effects of activin-A in the context of lung cancer, we utilized the OVA-expressing Lewis Lung Carcinoma mouse model as well as the B16F10 melanoma model of pulmonary metastases. The therapeutic potential of activin-A-treated lung tumor-infiltrating CD4+ T cells was evaluated in adoptive transfer experiments, using CD4-/--tumor bearing mice as recipients. In a reverse approach, we disrupted activin-A signaling on CD4+ T cells using an inducible model of CD4+ T cell-specific knockout of activin-A type I receptor. RNA-Sequencing analysis was performed to assess the transcriptional signature of these cells and the molecular mechanisms which mediate activin-A’s function. In a translational approach, we validated activin-A’s anti-tumorigenic properties using primary human tumor-infiltrating CD4+ T cells from lung cancer patients. Results: Administration of activin-A in lung tumor-bearing mice attenuated disease progression, an effect associated with heightened ratio of infiltrating effector to regulatory CD4+ T cells. Therapeutic transfer of lung tumor-infiltrating activin-A-treated CD4+ T cells, delayed tumor progression in CD4-/- recipients and enhanced T cell-mediated immunity. CD4+ T cells genetically unresponsive to activin-A, failed to elicit effective anti-tumor properties and displayed an exhausted molecular signature governed by the transcription factors Tox and Tox2. Of translational importance, treatment of activin-A on tumor-infiltrating CD4+ T cells from lung cancer patients augmented their immunostimulatory capacity towards autologous CD4+ and CD8+ T cells. Conclusions: In this study, we introduce activin-A as a novel immunomodulatory factor in the lung tumor microenvironment, which bestows exhausted CD4+ T cells with effector properties.
2021-09-10 | GSE183544 | GEO
Project description:BackgroundAlthough tumor-infiltrating T cells represent a favorable prognostic marker for cancer patients, the majority of these cells are rendered with an exhausted phenotype. Hence, there is an unmet need to identify factors which can reverse this dysfunctional profile and restore their anti-tumorigenic potential. Activin-A is a pleiotropic cytokine, exerting a broad range of pro- or anti-inflammatory functions in different disease contexts, including allergic and autoimmune disorders and cancer. Given that activin-A exhibits a profound effect on CD4+ T cells in the airways and is elevated in lung cancer patients, we hypothesized that activin-A can effectively regulate anti-tumor immunity in lung cancer.MethodsTo evaluate the effects of activin-A in the context of lung cancer, we utilized the OVA-expressing Lewis Lung Carcinoma mouse model as well as the B16F10 melanoma model of pulmonary metastases. The therapeutic potential of activin-A-treated lung tumor-infiltrating CD4+ T cells was evaluated in adoptive transfer experiments, using CD4-/--tumor bearing mice as recipients. In a reverse approach, we disrupted activin-A signaling on CD4+ T cells using an inducible model of CD4+ T cell-specific knockout of activin-A type I receptor. RNA-Sequencing analysis was performed to assess the transcriptional signature of these cells and the molecular mechanisms which mediate activin-A's function. In a translational approach, we validated activin-A's anti-tumorigenic properties using primary human tumor-infiltrating CD4+ T cells from lung cancer patients.ResultsAdministration of activin-A in lung tumor-bearing mice attenuated disease progression, an effect associated with heightened ratio of infiltrating effector to regulatory CD4+ T cells. Therapeutic transfer of lung tumor-infiltrating activin-A-treated CD4+ T cells, delayed tumor progression in CD4-/- recipients and enhanced T cell-mediated immunity. CD4+ T cells genetically unresponsive to activin-A, failed to elicit effective anti-tumor properties and displayed an exhausted molecular signature governed by the transcription factors Tox and Tox2. Of translational importance, treatment of activin-A on tumor-infiltrating CD4+ T cells from lung cancer patients augmented their immunostimulatory capacity towards autologous CD4+ and CD8+ T cells.ConclusionsIn this study, we introduce activin-A as a novel immunomodulatory factor in the lung tumor microenvironment, which bestows exhausted CD4+ T cells with effector properties.
| S-EPMC8454162 | biostudies-literature
Project description:The transforming growth factor-β (TGF-ꞵ) family member activin A (hereafter Activin-A) is overexpressed in many cancer types, often correlating with cancer-associated cachexia and poor prognosis. Activin-A secretion by melanoma cells indirectly impedes CD8+ T cell-mediated anti-tumor immunity and promotes resistance to immunotherapies, even though Activin-A can be proinflammatory in other contexts. To identify underlying mechanisms, we here analyzed the effect of Activin-A on syngeneic grafts of Braf mutant YUMM3.3 mouse melanoma cells and on their microenvironment using single-cell RNA sequencing. We found that the Activin-A-induced immune evasion was accompanied by a proinflammatory interferon signature across multiple cell types, and that the associated increase in tumor growth depended at least in part on pernicious STING activity within the melanoma cells. Besides corroborating a role for proinflammatory signals in facilitating immune evasion, our results suggest that STING holds considerable potential as a therapeutic target to mitigate tumor-promoting Activin-A signaling at least in melanoma.
2024-02-07 | GSE247228 | GEO
Project description:The transforming growth factor-β (TGF-ꞵ) family member activin A (hereafter Activin-A) is overexpressed in many cancer types, often correlating with cancer-associated cachexia and poor prognosis. Activin-A secretion by melanoma cells indirectly impedes CD8+ T cell-mediated anti-tumor immunity and promotes resistance to immunotherapies, even though Activin-A can be proinflammatory in other contexts. To identify underlying mechanisms, we here analyzed the effect of Activin-A on syngeneic grafts of Braf mutant YUMM3.3 mouse melanoma cells and on their microenvironment using single-cell RNA sequencing. We found that the Activin-A-induced immune evasion was accompanied by a proinflammatory interferon signature across multiple cell types, and that the associated increase in tumor growth depended at least in part on pernicious STING activity within the melanoma cells. Besides corroborating a role for proinflammatory signals in facilitating immune evasion, our results suggest that STING holds considerable potential as a therapeutic target to mitigate tumor-promoting Activin-A signaling at least in melanoma.
2024-02-07 | GSE247227 | GEO
Project description:Whole cell extracts from mouse Th17 cells treated with activin A were profiled with extensive fractionation and bottom-up proteomics
2020-05-18 | PXD017757 | Pride
Project description:Deleting DNMT3A in CAR T cells prevents exhaustion and 1 enhances antitumor activity
| PRJNA765208 | ENA
Project description:Carbohydrate Syntrophy enhances the establishment of Bifidobacterium breve UCC2003 in the neonatal gut
| PRJNA432716 | ENA
Project description:The failure of T-cells to control tumor growth has been associated with several functional defects that collectively lead to T-cell “exhaustion.” This phenotype results from chronic antigen stimulation within the tumor microenvironment, but how repetitive antigenic stimulation leads to T-cell exhaustion remains poorly defined. Here we show that persistent antigen stimulation induces mitochondrial oxidative stress that reduces tricarboxylic acid (TCA) cycle activity. The resultant bioenergetic compromise impairs nucleotide triphosphate synthesis, induces endoplasmic reticulum (ER) stress, and activates an exhaustion-associated gene expression program. Reversal of oxidative stress with N-acetylcysteine effectively restores T-cell proliferation, effector function, and memory-associated gene expression and enhances anti-tumor T-cell efficacy in vivo. These data reveal that induction of mitochondrial oxidative stress is a critical component of terminal T-cell dysfunction. Furthermore, treatments that restore mitochondrial redox are sufficient to prevent T-cell exhaustion and enhance anti-tumor immunity.
2020-05-21 | GSE138459 | GEO
Project description:Activin signalling controls the pluripotency of human embryonic stem cells (hESCs) by inducing the formation of nuclear Smad2/3-Nanog complexes that bind to and regulate several downstream targets. We aimed to clarify the transcriptional dynamics to the inhibition of Activin in hPSCs. To this end we performed microarray analysis of hPSCs treated with SB431542 (SB), an antagonist of the ALK4 and ALK7 type I Activin receptors, for early (2h, 4h and 8h) and late (24h and 48h) time points. Moreover, given our finding that Activin signalling regulates H3K4me3 of its target genes, we tested the transcriptional effect to the knock-down of the Mll/Set1 complex subunit Dpy30 by using shRNA. Finally, we also evaluated the transcriptional response to the knock-down of the Smad2/3 cofactor Nanog by using shRNA.
2015-01-01 | E-MTAB-2749 | biostudies-arrayexpress