Comparison of NKG2A+/- stimulated CD8 T cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB47938 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR6929090_1.fastq.gz | Fastqsanger.gz | |||
| ERR6929090_2.fastq.gz | Fastqsanger.gz | |||
| ERR6929091_1.fastq.gz | Fastqsanger.gz | |||
| ERR6929091_2.fastq.gz | Fastqsanger.gz | |||
| ERR6929092_1.fastq.gz | Fastqsanger.gz |
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Project description:Checkpoint blockage has revolutionized cancer treatment. NKG2A is an inhibitory receptor expressed by cytotoxic lymphocytes, including NK cells. In contrast to other checkpoint inhibitory antibodies, anti-NKG2A antibodies have shown only limited success. Here, we designed a Cas9-based strategy to delete KLRC1 from human NK cells. Electroporation of KLRC1-targeting Cas9-RNP efficiently eliminated NKG2A expression from primary human NK cells. NKG2A-deficient NK cells showed normal proliferation, only minor transcriptional changes related to enhanced NK cell activation and maintained their phenotype and licensing status. Genetic deletion of NKG2A fully bypassed HLA-E inhibition and further enhanced NK cell activity against various tumor cell lines, thereby outperforming anti-NKG2A antibodies. In combination with antibody-coating of tumor cells to induce antibody-dependent cellular cytotoxicity, genetic deletion of NKG2A independently promoted cytotoxicity. Thus, Cas9-mediated targeting of NKG2A is an effective way to target this important inhibitory checkpoint. This technique is easily amenable to adoptive cell therapy in the clinical setting, where NKG2A deletion will promote anti-tumor responses and may help NK cells to better infiltrate and persist in an inhibitory tumor microenvironment.
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Project description:New targets that enhance anti-tumor immunity must be identified to improve the efficacy of cancer immunotherapy. Here we show that loss of endoplasmic reticulum aminopeptidase (ERAP) family proteins improves anti-tumor immunity and synergizes with immune checkpoint blockade. Mechanistically, we show that loss of ERAP inactivates the HLA-E/NKG2A checkpoint, which normally restrains tumor killing by both CD8+ T cells and NK cells. The inhibitory activity of HLA-E is dependent on its presentation of a restricted set of invariant epitopes which form the binding surface for the NKG2A/CD94 receptor complex. Using genetic screening, in vivo models, cell-based assays, and immunopeptidomics, we show that loss of ERAP activity prevents the processing of these invariant peptides and alters the presented peptidome of both HLA-E and classical MHC-I. HLA-E neo-peptides presented after ERAP deletion are unable to bind the NKG2A/CD94 receptor, rendering tumor cells highly susceptible to killing by NKG2A+ cytotoxic T and NK cells. Thus, loss of ERAP phenocopies the loss or inhibition of the HLA-E/NKG2A pathway and represents an attractive therapeutic approach to inhibit this critical checkpoint. More broadly, this work identifies ERAP1/2 as druggable intracellular enzymes that could be targeted using small molecules to inactivate a cell-surface inhibitory pathway and represents a novel approach to therapeutic modulation of immune responses.
2024-11-21 | PXD052031 | Pride
Project description:Cancer immunotherapy is gaining increasing attention. However, immune checkpoints are exploited by cancer cells to evade anti-tumor immunotherapy. Here, we knocked out NKG2A, an immune checkpoint expressed on natural killer (NK) cells, in human pluripotent stem cells (hPSCs) and differentiated these hPSCs into NK (PSC-NK) cells. We show that NKG2A knockout (KO) enhances the anti-tumor and anti-viral capabilities of PSC-NK cells. NKG2A KO endows PSC-NK cells with higher cytotoxicity against HLA-E-expressing glioblastoma (GBM) cells, leukemia cells, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected cells in vitro. The NKG2A KO PSC-NK cells also exerted potent anti-tumor activity in vivo, leading to substantially suppressed tumor progression and prolonged survival of tumor-bearing mice in a xenograft GBM mouse model. These findings underscore the potential of PSC-NK cells with immune checkpoint KO as a promising cell-based immunotherapy. The unlimited supply and ease of genetic engineering of hPSCs makes genetically engineered PSC-NK an attractive option for easily accessible "off-the-shelf" cancer immunotherapy.
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Project description:A key mechanism of tumor resistance to immune cells is mediated by expression of peptide-loaded HLA-E in tumor cells, which suppresses natural killer (NK) cell activity via ligation of the NK inhibitory receptor CD94/NKG2A. To bypass HLA-E inhibition, we developed a way to generate highly functional NK cells lacking NKG2A. Constructs containing a single-chain variable fragment derived from an anti-NKG2A antibody were linked to endoplasmic reticulum-retention domains. After retroviral transduction in human peripheral blood NK cells, these NKG2A Protein Expression Blockers (PEBLs) abrogated NKG2A expression. The resulting NKG2Anull NK cells had higher cytotoxicity against HLA-E-expressing tumor cells.
2019-05-17 | GSE127081 | GEO
Project description:We studied the heterogeneity among human KIR/NKG2A+CD8+ T cells. First, we found that KIRs and NKG2A are expressed on human CD8+ T cells in a mutually exclusive manner. Therefore, we compared KIR+CD8+ and NKG2A+CD8+ T cells in regards to TCR overlap and transcriptomic profiles and demonstrated that KIR+CD8+ and NKG2A+CD8+ T cells are distinct innate-like populations.
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Project description:Tsao H, Anderson S, Finn KJ, Perera J, Pass LF, Schneider EM, Jiang A, Fetterman R, Chuong CL, Kozuma K, Stickler MM, Creixell M, Klaeger S, Phulphagar KM, Rachimi S, Verzani EK, Olsson N, Dubrot J, Pech MF, Silkworth W, Lane-Reticker SK, Allen PM, Ibrahim K, Knudsen NH, Cheng AY, Long AH, Ebrahimi-Nik H, Kim SY, Du PP, Iracheta-Vellve A, Robitschek EJ, Suermondt JSMT, Davis TGR, Wolfe CH, Atluri T, Olander KE, Rush JS, Sundberg TB, McAllister FE, Abelin JG, Firestone A, Stokoe D, Carr SA, Harding FA, Yates KB, Manguso RT. 2024
New targets that enhance anti-tumor immunity must be identified to improve the efficacy of cancer immunotherapy. Here we show that loss of endoplasmic reticulum aminopeptidase (ERAP) family proteins improves anti-tumor immunity and synergizes with immune checkpoint blockade. Mechanistically, we show that loss of ERAP inactivates the HLA-E/NKG2A checkpoint, which normally restrains tumor killing by both CD8+ T cells and NK cells. The inhibitory activity of HLA-E is dependent on its presentation of a restricted set of invariant epitopes which form the binding surface for the NKG2A/CD94 receptor complex. Using genetic screening, in vivo models, cell-based assays, and immunopeptidomics, we show that loss of ERAP activity prevents the processing of these invariant peptides and alters the presented peptidome of both HLA-E and classical MHC-I. HLA-E neo-peptides presented after ERAP deletion are unable to bind the NKG2A/CD94 receptor, rendering tumor cells highly susceptible to killing by NKG2A+ cytotoxic T and NK cells. Thus, loss of ERAP phenocopies the loss or inhibition of the HLA-E/NKG2A pathway and represents an attractive therapeutic approach to inhibit this critical checkpoint. More broadly, this work identifies ERAP1/2 as druggable intracellular enzymes that could be targeted using small molecules to inactivate a cell-surface inhibitory pathway and represents a novel approach to therapeutic modulation of immune responses.
2024-05-10 | MSV000094736 | MassIVE
Project description:Blockade of NKG2A/HLA-E interaction is a promising strategy to unleash the anti-tumor response. Yet the regulation of NKG2A expression on CD8+ lymphocytes and the T cell anti-tumor response are still poorly understood. Here, by performing CITE-seq on human T cells derived from head and neck squamous cell carcinoma and colorectal cancer, we show that NKG2A expression is induced in tumor-infiltrating CD8+ T cells differentiating into cytotoxic, CD39+CD103+ double positive (DP) T cells. This developmental trajectory lead to TCR repertoire overlap between the NKG2A– and NKG2A+ DP CD8 T cells, suggesting shared antigen specificities. Mechanistically, IL-12 is essential for the expression of the NKG2A on naïve CD8+ T cells in a CD40/CD40L- dependent manner, in conjunction with TCR stimulation and increased TGF-β levels. Our study thus reveals that NKG2A is induced by IL-12 on human tumor-reactive CD8+ T cells exposed to a TGF-b-rich environment, highlighting an underappreciated immuno-regulatory feedback loop dependent on IL-12 stimulation.
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Project description:We report abnormal pregnancy outcomes in mice lacking NKG2A, including altered placental transcription. In humans, we find HLAB-21T snp to be associated with an increased risk of pre-eclampsia.
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Project description:The ability to modulate immune-inhibitory pathways using checkpoint blockade antibodies such as PD-1, PD-L1, and CTLA-4 represents a significant breakthrough in cancer therapy in recent years. This has driven interest in identifying small-molecule-immunotherapy combinations to increase the proportion of responses. Murine syngeneic models, which have a functional immune system, represent an essential tool for pre-clinical evaluation of new immunotherapies. However, immune response varies widely between models and the translational relevance of each model is not fully understood, making selection of an appropriate pre-clinical model for drug target validation challenging. Utilizing RNAseq transcriptomic profiling, we have characterised the changes in gene regulatory pathways and immune populations in CT26 mice after treatment with the combination of anti-PD-L1 and anti-CTLA-4 antibodies. At day 7 post tumor implant, the pathways analysis of differentially expressed genes indicated an enrichment for migration of leukocytes in response to inflammation and communication between innate and adaptive immune cells. Similarly, analysis of upstream regulators suggested that lipopolysaccharide, IL-1B, TNF, IFNG, and NFKB1A pathways associated with inflammation were activated. At day 14, pathways related T-helper cell signalling pathways were upregulated. In addition, upstream regulators of the lipopolysaccharide and IFNG pathway, as well STAT1 and IL21 pathway were enriched, indicative of innate and adaptive immune response to inflammation.
2020-04-16 | E-MTAB-7777 | biostudies-arrayexpress
Project description:Results of combining radiotherapy/chemoradiotherapy and immune checkpoint blockade have been disappointing in patients with locally advanced head and neck squamous cell carcinoma (HNSCC). For such a potentially radiocurable disease, there remains an imperative to explore novel combination approaches. Here, we show that combining ATR inhibition with radiotherapy (ATRi/RT) increases the frequency of activated NKG2A/PD-1 double-positive T cells in animal models of HNSCC. Addition of dual anti-NKG2A/-PD-L1 blockade to ATRi/RT in the adjuvant, post-radiotherapy setting induces a robust antitumour response. Efficacy of the combination relies on CD40/CD40L costimulatory-mediated infiltration of activated/proliferative/memory CD8 and CD4 T cells with persistent or new T cell receptor (TCR) signalling, respectively. In this favourable therapeutic context, we reveal increased richness of the TCR repertoire and the emergence of numerous and large TCR clusters that share antigen specificity in response to combination therapy. Collectively, our data point towards promising combination approaches for future clinical testing in HNSCC.
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