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Induction of senescence renders cancer cells highly immunogenic

ABSTRACT: 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.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Cell Culture

SUBMITTER: Kevin Kovalchik

LAB HEAD: Manuel Serrano

PROVIDER: PXD034059 | Pride | 2022-11-09

REPOSITORIES: Pride

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Senescent cells display an altered immunopeptidome and promote CD8-dependent antitumor immunity

Project description:Cellular senescence is a stress response known to activate innate immunity. However, how senescent cells interact with the adaptive immune system remains largely unexplored. Here, we show that senescent cells display an enhanced MHC class I antigen processing and presentation. Furthermore, senescent cells present an altered immunopeptidome including unique non-mutated antigens that can be recognized by specific CD8 T cells. Immunization of mice with senescent cancer cells triggers strong protective CD8-dependent antitumor responses, superior to immunogenic cell death. Similarly, induction of senescence in human primary cancer cells hyperactivates their cognate reactive CD8 T cell. Our study indicates that immunization with senescent cells provides a sustained source of antigens that strongly activate anti-tumor CD8 T cells.

2022-10-18 | PXD033714 | Pride

Gene expression in LCMV-specific Blimp-1 deficient effector CD8+ T cells compared to wildtype effector CD8+ T cells

Project description:Antigen-specific effector CD8+ T cells deficient in Blimp-1 (Prdm1) do not acquire maximal effector functions, evade terminal differentiation, and more rapidly acquire some hallmark properties of memory CD8+ T cells. In this study, we compared the gene expression profiles of wildtype and Prdm1-/- LCMV-specific effector CD8+ T cells to better understand the molecular mechanisms underlying this striking phenotype. DNA microarray analysis was performed of DbGP33-41 and DbNP396-404 tetramer-positive effector CD8+ T cells FACS-sorted at day 8 post-LCMV infection from four independent samples of either Blimp-1 conditional knockout mice (CKO; Blimp-1flox/flox x GranzymeB-cre+) or wildtype (WT) littermate controls.

2010-08-19 | E-GEOD-17211 | biostudies-arrayexpress

Transcription profiling of human BRAFE600-induced senescent, senescence bypassing, and quiescent fibroblast cells, compared to cycling cells

Project description:Analysis of BRAFE600-induced senescent, senescence bypassing, and quiescent cells, all compared to cycling cells.

2008-06-13 | E-NCMF-12 | biostudies-arrayexpress

Comparison of senescence bypass

Project description:Analysis of BRAFE600 induced senescence bypassing cells due to C/EBPbeta or TSC22D1 depletion, compared to BRAFE600 senescent cells.

2011-11-05 | E-MTAB-441 | biostudies-arrayexpress

Typhoid toxin hijacks Wnt5a to potentiate TGFβ-mediated senescence and Salmonella infection

Project description:Damage to our genome causes acute senescence in mammalian cells, which undergo growth arrest and release a secretome that elicits cell cycle arrest in bystander cells through the senescence-associated secretory phenotype (SASP). Thus, acute senescence is a powerful tumour suppressor. Salmonella enterica hijacks senescence through its typhoid toxin, which usurps unidentified factors in the stress secretome of senescent cells to mediate intracellular infections. Here, transcriptomics of toxin-induced senescent cells (txSCs) and proteomics of their secretome identified secreted ligands that activate the TGFβ pathway through SMAD transcription factors. The ligand Wnt5a established a self-amplifying positive feedback loop driving TGFβ signalling, which enforced autocrine senescence in txSCs and paracrine senescence in naive bystander cells by activation of DDRs. Wnt5a and GDF15 increased host cell susceptibility to infection. The study reveals how an innate defence against cancer is co-opted by a bacterial pathogen to cause widespread damage and mediate infections.

2023-09-07 | PXD037373 | Pride

MHC-IP MS of EpiScan A02 SARS-CoV-2 library

Project description:Identification of CD8+ T-cell epitopes is critical for the development of immunotherapeutics. Existing methods for MHC-I ligand discovery are time-intensive, specialized and unable to interrogate specific proteins on a large scale. Here we present EpiScan, which uses surface MHC-I levels as a readout for whether a genetically encoded peptide is an MHC-I ligand. Oligonucleotide synthesis permits facile screening for MHC-I ligands amongst predetermined starting pools comprising >100,000 peptides. We exploit this programmability of EpiScan to uncover an unappreciated role for cysteine that increases the number of predicted ligands by 12-21%, reveal affinity hierarchies by analysis of biased-anchor peptide libraries, and screen viral proteomes for MHC-I ligands. Using these data, we generate and iteratively refine peptide binding prediction predictions to create EpiScan Predictor, or ESP. ESP performed comparably to other state-of-the-art MHC-I peptide binding prediction algorithms while not suffering from underrepresentation of cysteine-containing peptides. Thus, targeted immunopeptidomics using EpiScan will accelerate CD8+ T-cell epitope discovery towards the goal of patient-specific immunotherapeutics.

2022-10-13 | PXD036939 | Pride

Comparison of gene expression profiles of HIV-specific CD8 T cells from controllers and progressors

Project description:CD8+ T cells in chronic viral infections like HIV develop functional defects such as loss of IL-2 secretion and decreased proliferative potential that are collectively termed exhaustion1. Exhausted T cells express increased levels of multiple inhibitory receptors, such as Programmed Death 1 (PD-1). PD-1 inhibition contributes to impaired virus-specific T cell function in chronic infection because antibody-mediated blockade of its ligand, Programmed Death Ligand 1 (PD-L1) is sufficient to improve T cell function and reduce viral replication in animal models. Reversing PD-1 inhibition is therefore an attractive therapeutic target, but the cellular mechanisms by which PD-1 ligation results in T cell inhibition are not fully understood. PD-1 is thought to limit T cell activation by attenuating T cell receptor (TCR) signaling. It is not known whether PD-1 ligation also acts by upregulating genes in exhausted T cells that impair their function. Here, we analyzed gene-expression profiles from HIV-specific CD8+ T cells in patients with HIV and show that PD-1 coordinately upregulates a program of genes in exhausted CD8+ T cells from humans and mice. This program includes upregulation of basic leucine transcription factor, ATF-like (BATF), a transcription factor in the AP-1 family. Enforced expression of BATF was sufficient to impair T cell proliferation and cytokine secretion, while BATF knockdown reduced PD-1 inhibition. Silencing BATF in CD4+ and CD8+ T cells from chronic viremic patients rescued HIV-specific T cell function. Thus inhibitory receptors can cause T cell exhaustion by upregulating genes â such as BATF â that inhibit T cell function. We sorted HIV-specific CD8+ T cells from 18 progressors and 24 controllers, cohorts with a two-log difference in mean viral load

2010-10-03 | E-GEOD-24081 | biostudies-arrayexpress

The self-peptide repertoire plays a critical role in transplant tolerance induction

Project description:While direct allorecognition underpins both solid organ allograft rejection and tolerance induction, the specific molecular targets of most directly-alloreactive CD8+ T cells have not been defined. In this study, we used a combination of genetically-engineered MHC I constructs, mice with a hepatocyte-specific mutation in the class I antigen-presentation pathway and immunopeptidomic analysis to provide definitive evidence for the contribution of the peptide cargo of allogeneic MHC I molecules to transplant tolerance induction. We established a systematic approach for the discovery of directly-recognised pMHC epitopes, and identified 17 strongly immunogenic H-2Kb-associated peptides recognised by CD8+ T cells from B10.BR (H-2k) mice, 13 of which were also recognised by BALB/c (H-2d) mice. As few as five different tetramers used together were able to identify almost 40% of alloreactive T cells within a polyclonal population. To our knowledge, this represents the first example of such an approach in the context of direct allorecognition.

2021-12-06 | PXD022695 | Pride

The self-peptide repertoire plays a critical role in transplant tolerance induction

2021-12-06 | PXD023015 | Pride

Proteomic identification of MHC class I-associated peptidome derived from non-obese diabetic mouse thymus and pancreas

Project description:The peptides repertoire presented to CD8+ T cells by major histocompatibility complex (MHC) class I molecules, referred to as the MHC I-associated peptidome (MIP), regulates all critical events that occur during the lifetime of CD8+ T cells. The MIP presented by thymic antigen presenting cells (APCs) is crucial for shaping CD8+ T cell repertoire and self-tolerance, while the MIP presented by peripheral tissues and organs is not only involved in maintaining periphery CD8+ T cell survival and homeostasis, but also mediates immune surveillance and autoimmune responses of CD8+ T cells under pathological conditions. Type 1 diabetes (T1D) is an organ-specific autoimmune disease caused by the destruction pancreatic β cells, mediated primarily by autoreactive CD8+ T cells. Non-obese diabetic (NOD) mouse is one of important animal models of spontaneous autoimmune diabetes that shares several key features with human T1D. Here, we deeply analyzed the MIP derived from the primary tissues of thymus and pancreas in NOD mice using targeted database searches of mass spectrometry data. We demonstrated that the thymus MIP source proteins accommodated only a small portion of the transcriptome of thymus epithelial cells, and partially shared with the MIP source proteins derived from NOD mice pancreas and β cell line. The global view of the MHC I-associated self-peptides repertoire in the thymus and pancreas of NOD mice may serve as a biological reference to identify potential autoantigens targeted by autoreactive CD8+ T cells in T1D.

2022-10-14 | PXD031966 | Pride

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