Senescent cells display an altered immunopeptidome and promote CD8-dependent antitumor immunity
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Q Exactive HF-X, Q Exactive HF
ORGANISM(S): Homo Sapiens (human) Mus Musculus (mouse)
TISSUE(S): Epithelial Melanocyte, Embryonic Fibroblast, Fibroblast Of Lung
SUBMITTER: 
Eduardo Zarzuela
LAB HEAD: Javier Muñoz Peralta
PROVIDER: PXD033714 | Pride | 2022-10-18
REPOSITORIES: Pride
Similar Datasets
Project description:Cellular senescence is a stress response that activates innate immunity. However, the interplay between senescent cells and the adaptive immune system remains largely unexplored. Here, we show that senescent cells display enhanced MHC class I (MHC-I) antigen processing and presentation. Immunization of mice with senescent syngeneic fibroblasts generates CD8 T cells reactive against both normal and senescent fibroblasts, some of them targeting senescence-associated MHC-I-peptides. In the context of cancer, we demonstrate that senescent cancer cells trigger strong anti-tumor protection mediated by antigen-presenting cells and CD8 T cells. This response is superior to the protection elicited by cells undergoing immunogenic cell death. Finally, induction of senescence in patient-derived cancer cells exacerbates the activation of autologous tumor-reactive CD8 tumor-infiltrating lymphocytes (TILs) with no effect on non-reactive TILs. Our study indicates that immunization with senescent cancer cells strongly activates anti-tumor immunity, and this can be exploited for cancer therapy.
2022-11-09 | PXD034059 | Pride
Project description:Senescence is a permanent cell cycle arrest that occurs in response to cellular stress. Because senescent cells promote age-related disease, there has been considerable interest in defining the proteomic alterations in senescent cells. Because senescence differs greatly depending on cell type and senescence inducer, continued progress in the characterization of senescent cells is needed. Here, we analyzed primary human mammary epithelial cells (HMECs), a model system for aging, using mass spectrometry-based proteomics. By integrating data from replicative senescence, immortalization by telomerase reactivation, and drug-induced senescence, we identified a robust proteomic signature of HMEC senescence consisting of 77 upregulated and 36 downregulated proteins. This approach identified known biomarkers, such as downregulation of the nuclear lamina protein lamin-B1 (LMNB1), and novel upregulated proteins including the β-galactoside-binding protein galectin-7 (LGALS7). Gene ontology enrichment analysis demonstrated that senescent HMECs upregulated lysosomal proteins and downregulated RNA metabolic processes. We additionally integrated our proteomic signature of senescence with transcriptomic data from senescent HMECs to demonstrate that our proteomic signature can discriminate proliferating and senescent HMECs even at the transcriptional level. Taken together, our results demonstrate the power of proteomics to identify cell type-specific signatures of senescence and advance the understanding of senescence in primary HMECs.
2021-09-28 | PXD027318 | Pride
Project description:<p><strong>BACKGROUND:</strong> Periodontal ligament mesenchymal stem cells (PDLSCs) are a promising cell resource for cell-based regenerative medicine in dentistry. PDLSCs inevitably acquire a senescent phenotype after prolonged in vitro expansion, and the key regulators of cells during replicative senescence remain unclear.</p><p><strong>METHODS:</strong> We cultured periodontal ligament stem cells to passages 4, 10 and 20 (P4, P10, P20). The senescent phenotypes, proliferation and migration ability of PDLSCs (P4, P10, P20) were detected, and non-targeted metabonomic sequencing was performed. We treated PDLSCs with AICAR and detected the expression of FOXO1, FOXO3a, FOXO6 and AMPK phosphorylation (p-AMPK) levels of replicating senescent PDLSCs to explore the correlation between the metabolic changes and the AMPK pathway.</p><p><strong>RESULTS:</strong> Immunofluorescence staining of γ-H2AX, β-galactosidase staining, cell scratch test and qPCR were performed to confirm the occurrence of replicative senescence in PDLSCs during passaging. Three groups of cells at passage 4 (P4), passage 10 (P10) and passage 20 (P20) were collected for non-targeted metabolomics analysis. Metabonomic sequencing showed that the metabolism of replicative senescence in PDLSCs varied significantly. In particular, the content of fatty acid metabolites decreased with senescence, including capric acid, stearic acid, myristic acid and dodecanoic acid. KEGG pathway analysis showed that the AMPK signaling pathway was closely related to AMP levels. The AMP:ATP ratio increased in senescent PDLSCs; however, the levels of p-AMPK and the profile of FOXO1 and FOXO3a, which are downstream of the AMPK signaling pathway, decreased with senescence. We treated PDLSCs with AICAR, an activator of the AMPK pathway, and the phosphorylated AMPK level at P20 PDLSCs was partially restored. </p><p><strong>CONCLUSION:</strong> In summary, our study suggests that the metabolic process of PDLSCs is active in the early stage of senescence, prefers to consume fatty acids, and is attenuated in the later stages of senescence. AMP accumulates in replicative senescent PDLSCs; however, the sensitivity of AMPK phosphorylation sites is impaired, causing senescent PDLSCs to fail to respond to changes in energy metabolism. Our findings provide a new basis for the clinical application of periodontal ligament stem cells.</p>
2022-11-15 | MTBLS4568 | MetaboLights
Project description:Cytokinins are plant hormones with biological functions ranging from coordination of plant growth and development to the regulation of senescence. A series of 2-chloro-N6-(halogenobenzylamino)purine ribosides was prepared and tested for cytokinin activity in selected bioassays. Several compounds showed significant activity, especially in delaying senescence in detached wheat leaves. We used microarrays to gather information about the reprogramming of gene transcription when senescent Arabidopsis leaves were treated with selected C2-substituted aromatic cytokinin ribosides that showed high activity in the senescence bioassay. Arabidopsis senescent leaves were treated with cytokinins and subsequently used for RNA extraction and hybridization on Affymetrix microarrays. 21-days old Arabidopsis leaves were treated with the appropriate cytokinin or left untreated (DMSO only).
2015-12-11 | E-GEOD-75875 | biostudies-arrayexpress
Project description:Oncogene-induced senescence provides a barrier against malignant transformation. Senescent cells secrete pro-inflammatory cytokines, chemokines and growth factors collectively known as the senescence-associated secretory phenotype (SASP). Paradoxically, the SASP can also negatively impact the neighbouring tissues through inducing an inflammatory environment that promotes tumorigenesis and aged-related pathologies. We have previously shown that the lncRNA MIR31HG is overexpressed and located in the cytoplasm during BRAF-induced senescence. In young proliferating cells, nuclear MIR31HG inhibits p16/CDKN2A expression through interaction with polycomb repressor complexes (PRC1/2). Here, we show that MIR31HG regulates the expression and secretion of a subset of SASP components during BRAF-induced senescence. The SASP secreted from senescent cells depleted for MIR31HG fails to induce paracrine invasion without affecting the growth inhibitory effect. Mechanistically, MIR31HG interacts with the translation factor YBX1 facilitating its phosphorylation at serine 102 (p-YBX1S102) by the kinase RSK. p-YBX1S102 induces IL1A translation which acts as upstream regulator inducing the transcription of the other SASP mRNAs. Our results suggest a dual role for MIR31HG in senescence depending on its cellular localization and place the lncRNA as a potential therapeutic target in the treatment of senescence-related pathologies.
2021-03-02 | PXD017475 | Pride
Project description:Cellular senescence involves a stable cell cycle arrest coupled to a secretory program that, in some instances, stimulates the immune clearance of senescent cells. Using an immune competent tumor model in which senescence triggers CD8 T cell-mediated tumor rejection, we show that senescence also remodels cell surface proteome to alter how they sense environmental factors, as exemplified by Type II interferon gamma (IFN-γ). Compared to proliferating cells, senescent cells upregulate IFN-γ receptor, become hypersensitized to microenvironmental IFN-γ, and more robustly induce antigen presenting machinery -effects also recapitulated in human tumor cells treated with senescence-inducing drugs. Disruption of the IFN-γ sensing by senescent cells blunts their immune-mediated clearance without disabling their characteristic secretory program or immune cell recruitment. Our results demonstrate that senescent cells have an enhanced ability to both send and receive environmental signals, and imply that each process is required for their effective immune surveillance.
2023-01-17 | GSE203140 | GEO
Project description:Cellular senescence involves a stable cell cycle arrest coupled to a secretory program that, in some instances, stimulates the immune clearance of senescent cells. Using an immune competent tumor model in which senescence triggers CD8 T cell-mediated tumor rejection, we show that senescence also remodels cell surface proteome to alter how they sense environmental factors, as exemplified by Type II interferon gamma (IFN-γ). Compared to proliferating cells, senescent cells upregulate IFN-γ receptor, become hypersensitized to microenvironmental IFN-γ, and more robustly induce antigen presenting machinery -effects also recapitulated in human tumor cells treated with senescence-inducing drugs. Disruption of the IFN-γ sensing by senescent cells blunts their immune-mediated clearance without disabling their characteristic secretory program or immune cell recruitment. Our results demonstrate that senescent cells have an enhanced ability to both send and receive environmental signals, and imply that each process is required for their effective immune surveillance.
2023-01-28 | GSE223874 | GEO
Project description:In arthritis, synovial fibroblast (SF) senescence is linked to the activation of a pro-inflammatory phenotype contributing to chronic arthritis pathogenesis. Additionally, senescent cells accumulate in ageing tissues further promoting ageing and inflammation. These cells have dysregulated mitochondrial function and metabolism, limited tissue regeneration, produce reactive oxygen species (ROS) and secrete bioactive molecules, including pro-inflammatory cytokines, chemokines and matrix-remodelling enzymes known as SASP (senescence-associated secretory phenotype). In vitro, senescent cells can induce a senescent phenotype in surrounding bystander cells. Interestingly, extracellular vesicles (EVs) have critical roles in cellular senescence and ageing and are mediators in intercellular communication. We hypothesize that senescent cells in osteoarthritic SFs induce senescence and/or a proinflammatory phenotype in non-senescent osteoarthritic SFs, mediated through EV cargo.
2022-10-15 | PXD032757 | Pride
Project description:Aging leads to a progressive functional decline of the immune system, rendering the elderly increasingly susceptible to disease and infection. The degree to which immune cell senescence contributes to this decline remains unclear, however, since markers that label immune cells with classical features of cellular senescence accurately and comprehensively have not been identified. Using a second‐generation fluorogenic substrate for β‐galactosidase and multi‐parameter flow cytometry, we demonstrate here that peripheral blood mononuclear cells (PBMCs) isolated from healthy humans increasingly display cells with high senescence‐associated β‐galactosidase (SA‐βGal) activity with advancing donor age. The greatest age‐associated increases were observed in CD8+ T‐cell populations, in which the fraction of cells with high SA‐βGal activity reached average levels of 64% in donors in their 60 s. CD8+ T cells with high SA‐βGal activity, but not those with low SA‐βGal activity, were found to exhibit features of telomere dysfunction‐induced senescence and p16‐mediated senescence, were impaired in their ability to proliferate, developed in various T‐cell differentiation states, and had a gene expression signature consistent with the senescence state previously observed in human fibroblasts. Based on these results, we propose that senescent CD8+ T cells with classical features of cellular senescence accumulate to levels that are significantly higher than previously reported and additionally provide a simple yet robust method for the isolation and characterization of senescent CD8+ T cells with predictive potential for biological age.
2021-04-14 | GSE169009 | GEO
Project description:Tissues are maintained by homeostatic feedback mechanisms in which cells can respond to, but also modify, the chemical and mechanical properties of the surrounding extracellular matrix (ECM). Mechano-sensitive mesenchymal stem cells (MSCs) resident in the marrow niche experience a diverse mechanical environment, but ageing can affect the composition and quality of bone and marrow tissues. Here we quantified the compounded effects of substrate stiffness and replication-induced senescence on MSC morphology and their ability to modify their environments through secretion of ECM proteins. The ECM proteome was found to be sensitive to substrate stiffness, but pharmacological inhibition of cellular contractility perturbed this response, decreasing levels of tenascin-C, fibulins and fibronectin. A corresponding change in the ECM of senescent cells, concomitant with a loss of mechano-responsive morphological features, suggested a decoupling of mechanotransduction pathways. Intracellular proteomic and transcriptomic analyses confirmed a decrease in all components of the cytoskeletal protein homeostasis machinery in senescent MSCs. These results demonstrate a senescence-mediated perturbation to cytoskeletal homeostasis, pathways of mechanotransduction and the secretion of ECM proteins considered necessary for tissue maintenance.
2022-10-10 | PXD013241 | Pride