IL-12 drives the expression of the inhibitory receptor NKG2A on human tumor-reactive CD8 T cells
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PROVIDER: PRJNA1168444 | ENA |
REPOSITORIES: ENA
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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.
2024-10-08 | GSE278692 | GEO
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: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: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.
2021-09-01 | GSE178566 | GEO
Project description:Blocking expression of inhibitory receptor NKG2A overcomes tumor resistance to NK cells
| PRJNA524164 | ENA
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: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.
2023-02-23 | GSE185567 | GEO
Project description:Inhibitory receptors (IR) are a diverse group of cell surface molecules that modulate T cell activation, but there are gaps in our knowledge of the cell extrinsic factors that regulate their expression. The present study found that in vivo overexpression of IL-27 led to increased T cell expression of PD-L1, LAG-3, TIGIT, and TIM-3. In vitro, TCR stimulation alone promoted expression of multiple IRs, while IL-27 alone induced expression of PD-L1. However, the combination of intermediate TCR stimulation and IL-27 resulted in synergistic induction of LAG-3, CTLA-4, and TIGIT. In vivo, infection with Toxoplasma gondii resulted in parasitespecific effector T cells that expressed high levels of IR and at local sites of infection where IL-27 production was highest, IL-27 was required for maximal effector cell expression of PD-L1, LAG-3, CTLA-4 and TIGIT. Together, these results affirm the critical role of TCR signals in the induction of IR expression, but find that during infection, IL-27 provides a signal that promotes T cell expression of inhibitory receptors.
2019-01-17 | GSE124222 | GEO
Project description:Viral vectors are attractive vaccine platforms that elicit robust innate and adaptive immune responses; however, viral vector vaccine candidates vary greatly in their ability to induce protective immunity. Ad5 vectors elicit robust CD8+ T cell responses but typically characterized by an exhausted phenotype. The mechanisms by which Ad5 vectors induce dysfunctional CD8+ T cells have not been fully elucidated. Here we demonstrate that Ad5 vectors, but not Ad26 vectors, elicit exhausted antigen-specific IL-10+PD1+ CD4+ T cells with a dysfunctional transcriptional profile, and these cells effectively suppress CD8+ T cells responses in vivo. Induction of inhibitory CD4+ T cells by Ad5 vectors was associated with increased IL-27 expression, and IL-27 blockade improved CD4+ T cell polyfunctionality. Together our data highlight a novel role for IL-27 in regulating responses to viral vector vaccines. Splenic CD45.2+ OT-II TCR-Tg CD4 T cells from CD45.1+ B6 mice immunized with Ad5-OVA or Ad26-OVA were purified by FACS on day 10 post-immunization
2016-06-01 | E-GEOD-73118 | biostudies-arrayexpress
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.
2024-10-18 | GSE241039 | GEO