Antigen cross-presentation in young tumor-bearing hosts promotes CD8 T cell terminal differentiation [gene expression]
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ABSTRACT:
PROVIDER: PRJNA778718 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR16859647_1.fastq.gz | Fastqsanger.gz | |||
| SRR16859647_2.fastq.gz | Fastqsanger.gz | |||
| SRR16859648_1.fastq.gz | Fastqsanger.gz | |||
| SRR16859648_2.fastq.gz | Fastqsanger.gz | |||
| SRR16859649_1.fastq.gz | Fastqsanger.gz |
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Project description:Antigen cross-presentation in young tumor-bearing hosts promotes CD8 T cell terminal differentiation
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Project description:Antigen cross-presentation in young tumor-bearing hosts promotes CD8 T cell terminal differentiation [WGBS]
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Project description:The immune system undergoes a progressive functional remodeling with age, polarizing the immune responses toward a “killer” or “healer” phenotype. Understanding how the age bias shapes anti-tumor immunity is essential in designing effective immunotherapies. In this manuscript we explore the anti-tumor CD8+ T cell responses generated in young (prepubescent) and adult (pre-senescent) mice. Using an MHCI-deficient, trackable tumor model, we observed that tumor reactive CD8+ T cells that expanded in young tumor-bearing (TB) mice acquired a terminally differentiated phenotype characterized by overexpression of inhibitory receptors and the transcription factor Tox1. Furthermore, tumor infiltrating CD8+ T cells from young tumors yielded a poor cytokine response compared to CD8+ T cells infiltrating adult tumors. Young migratory dendritic cells (migDC) and mononuclear phagocytic cells (MPCs) infiltrating young tumors were more competent in capturing and cross-presenting tumor antigen, leading to enhanced priming of CD8+ T cells in the draining lymph nodes (dLNs), and their subsequent terminal differentiation in the tumors. Notably, single-cell transcriptional profiling of tumor infiltrating MPCs revealed that young MPCs are polarized toward an inflammatory, effector phenotype. Consistent with our observations in young vs adult TB mice, analysis of immune infiltrates from pediatric solid tumors revealed a significant correlation between tumor-infiltrating CD8+ T cells with an exhaustion phenotype and the frequency of PD-L1-expressing phagocytic cells. Collectively, these data indicate that the young microenvironment of an actively developing tissue contributes to the generation of an immune response skewed toward a terminal effector state, thus narrowing the window for immunotherapeutic interventions.
2022-02-28 | GSE188388 | GEO
Project description:The immune system undergoes a progressive functional remodeling with age, polarizing the immune responses toward a “killer” or “healer” phenotype. Understanding how the age bias shapes anti-tumor immunity is essential in designing effective immunotherapies. In this manuscript we explore the anti-tumor CD8+ T cell responses generated in young (prepubescent) and adult (pre-senescent) mice. Using an MHCI-deficient, trackable tumor model, we observed that tumor reactive CD8+ T cells that expanded in young tumor-bearing (TB) mice acquired a terminally differentiated phenotype characterized by overexpression of inhibitory receptors and the transcription factor Tox1. Furthermore, tumor infiltrating CD8+ T cells from young tumors yielded a poor cytokine response compared to CD8+ T cells infiltrating adult tumors. Young migratory dendritic cells (migDC) and mononuclear phagocytic cells (MPCs) infiltrating young tumors were more competent in capturing and cross-presenting tumor antigen, leading to enhanced priming of CD8+ T cells in the draining lymph nodes (dLNs), and their subsequent terminal differentiation in the tumors. Notably, single-cell transcriptional profiling of tumor infiltrating MPCs revealed that young MPCs are polarized toward an inflammatory, effector phenotype. Consistent with our observations in young vs adult TB mice, analysis of immune infiltrates from pediatric solid tumors revealed a significant correlation between tumor-infiltrating CD8+ T cells with an exhaustion phenotype and the frequency of PD-L1-expressing phagocytic cells. Collectively, these data indicate that the young microenvironment of an actively developing tissue contributes to the generation of an immune response skewed toward a terminal effector state, thus narrowing the window for immunotherapeutic interventions.
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2022-02-28 | GSE188389 | GEO
Project description:The immune system undergoes a progressive functional remodeling with age. Understanding how age bias shapes antitumor immunity is essential in designing effective immunotherapies, especially for pediatric patients. Here, we explore antitumor CD8+ T cell responses generated in young (prepubescent) and adult (presenescent) mice. Using an MHCI-deficient tumor model, we observed that tumor-reactive CD8+ T cells expanded in young tumor-bearing (TB) mice acquired a terminally differentiated phenotype characterized by overexpression of inhibitory receptors and the transcription factor Tox1. Furthermore, tumor-infiltrating CD8+ T cells from young tumors yielded a poor cytokine response compared with CD8+ T cells infiltrating adult tumors. Young migratory dendritic cells (migDCs) from the draining lymph nodes (dLNs), and mononuclear phagocytic cells (MPCs) infiltrating young tumors, were more competent in capturing and cross-presenting tumor antigen, leading to enhanced priming of CD8+ T cells in dLNs and their subsequent terminal differentiation in the tumors. Single-cell transcriptional profiling of tumor-infiltrating MPCs demonstrated that young MPCs are polarized toward an inflammatory, effector phenotype. Consistent with our observations in young versus adult TB mice, analysis of immune infiltrates from pediatric solid tumors showed a correlation between tumor-infiltrating CD8+ T cells with an exhaustion phenotype and the frequency of PD-L1-expressing monocytes/macrophages. Collectively, these data indicate that a young tissue microenvironment contributes to the generation of an immune response skewed toward a less pliable terminal effector state, thus narrowing the window for immunotherapeutic interventions.
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Project description:Sca1+/cKit– hematopoietic BMCs of hosts bearing primary tumors promote the growth of distant tumors that form with a myofibroblast-rich, desmoplastic stroma. BMCs from old mice bearing primary tumors lack this ability
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Project description:Sca1+/cKitâ hematopoietic BMCs of hosts bearing primary tumors promote the growth of distant tumors that form with a myofibroblast-rich, desmoplastic stroma. BMCs from old mice bearing primary tumors lack this ability Sca1+/cKit- BMCs were isolated from young and old mice bearing Matrigel control or size-matched primary tumors by FACS directly into RLT Plus Buffer (Qiagen Rneasy Plus Micro Kit)
2016-07-21 | E-GEOD-74120 | biostudies-arrayexpress
Project description:Increased antigen cross-presentation but impaired cross-priming after activation of PPARγ is mediated by up-regulation of B7H1 Dendritic cells (DCs) are able to take up exogenous antigens and present antigen-derived peptides on MHC class I molecules, a process termed cross-presentation. The mannose receptor (MR), an endocytic receptor expressed on a variety of antigen-presenting cells (APCs), has been demonstrated to target soluble antigens exclusively towards cross-presentation. In this study, we investigated the role of the murine nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ), a ligand-activated transcription factor with immunomodulatory properties, in MR-mediated endocytosis and cross-presentation of the model antigen ovalbumin (OVA). We could demonstrate both in vitro and in vivo that activation of PPARγ resulted in increased MR expression, which in consequence led to enhanced MR-mediated endocytosis and elevated cross-presentation of soluble OVA. Concomitantly, activation of PPARγ in DCs induced up-regulation of the co-inhibitory molecule B7H1, which, despite enhanced cross-presentation, caused an impaired activation of naive OVA-specific CD8+ T cells and the induction of T cell tolerance. These data provide a mechanistic basis for the immunomodulatory action of PPARγ which might open new possibilities in development of therapeutical approaches aimed at the control of excessive immune responses, e.g. in T cell-mediated autoimmunity. Comparison of murine mannose receptor negative versus mannose receptor positive bone marrow-derived DCs
2010-05-08 | E-GEOD-15616 | biostudies-arrayexpress
Project description:Increased antigen cross-presentation but impaired cross-priming after activation of PPARγ is mediated by up-regulation of B7H1 Dendritic cells (DCs) are able to take up exogenous antigens and present antigen-derived peptides on MHC class I molecules, a process termed cross-presentation. The mannose receptor (MR), an endocytic receptor expressed on a variety of antigen-presenting cells (APCs), has been demonstrated to target soluble antigens exclusively towards cross-presentation. In this study, we investigated the role of the murine nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ), a ligand-activated transcription factor with immunomodulatory properties, in MR-mediated endocytosis and cross-presentation of the model antigen ovalbumin (OVA). We could demonstrate both in vitro and in vivo that activation of PPARγ resulted in increased MR expression, which in consequence led to enhanced MR-mediated endocytosis and elevated cross-presentation of soluble OVA. Concomitantly, activation of PPARγ in DCs induced up-regulation of the co-inhibitory molecule B7H1, which, despite enhanced cross-presentation, caused an impaired activation of naive OVA-specific CD8+ T cells and the induction of T cell tolerance. These data provide a mechanistic basis for the immunomodulatory action of PPARγ which might open new possibilities in development of therapeutical approaches aimed at the control of excessive immune responses, e.g. in T cell-mediated autoimmunity.
2009-06-19 | GSE15616 | GEO