KIR2DS2 B cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB49119 | ENA |
REPOSITORIES: ENA
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Project description:Background: T cell-based immunotherapies including immune checkpoint blockade (ICB) and chimeric antigen receptor (CAR) T cells can induce durable responses in cancer patients. However, clinical efficacy is limited due to the ability of cancer cells to evade immune surveillance. While T cells have been the primary focus of immunotherapy, recent research has highlighted the importance of Natural Killer (NK) cells in directly recognizing and eliminating tumor cells and playing a key role in the set-up of an effective adaptive immune response. The remarkable potential of NK cells for cancer immunotherapy is demonstrated by their ability to broadly identify stressed cells, irrespective of the presence of neoantigens, and their ability to fight tumors that have lost their Major Histocompatibility Complex class I (MHC I) expression due to acquired resistance mechanisms.
However, like T cells, NK cells can become dysfunctional within the tumor microenvironment. Strategies to enhance and reinvigorate NK cell activity hold potential for bolstering cancer immunotherapy.
Method: In this study, we conducted a high-throughput screen to identify molecules that could enhance primary human NK cell function. After compound validation, we investigated the effect of the top performing compound on dysfunctional NK cells that were generated by a newly developed in vitro platform. Functional activity of NK cells was investigated utilizing compounds alone and in combination with checkpoint inhibitor blockade. The findings were validated on patient-derived intratumoral dysfunctional NK cells from different cancer types.
Results: The screening approach led to the identification of a Cbl-b inhibitor enhancing the activity of primary human NK cells. Furthermore, the Cbl-b inhibitor was able to reinvigorate the activity of in vitro generated and patient-derived dysfunctional NK cells. Finally, Cbl-b inhibition combined with TIGIT blockade further increased the cytotoxic potential and reinvigoration of both in vitro generated and patient-derived intratumoral dysfunctional NK cells.
Conclusion: These findings underscore the relevance of Cbl-b inhibition in overcoming NK cells dysfunctionality with the potential to complement existing immunotherapies and improve outcomes for cancer patients.
2024-08-12 | MSV000095572 | MassIVE
Project description:We determined the global expression profile of DNAM-1+ and DNAM-1- NK cell purified by flow cytometry from 6 different groups of C57BL/6 WT mice. Natural killer (NK) cells comprise a heterogeneous population of cells important for pathogen defense and cancer surveillance. However, the functional significance of this diversity is not fully understood. Here, we demonstrate through transcriptional profiling and functional studies that the activating receptor DNAM-1 (CD226) identifies two distinct NK cell functional subsets: DNAM-1+ and DNAM-1- NK cells. DNAM-1+ NK cells have enhanced Interleukin 15 signaling, proliferate vigorously and produce high levels of inflammatory cytokines. By contrast, DNAM-1- NK cells that differentiate from DNAM-1+ NK cells, have greater expression of NK cell receptor related genes and are higher producers of chemokines. Together our findings highlight the existence of two distinct effector programs in innate lymphocytes controlled through DNAM-1 expression. NK1.1+NKp46+CD3- DNAM-1+ and DNAM-1- NK cell were purified by flow cytometry from 6 different groups of C57BL/6 WT mice and total RNA were extracted
2015-02-26 | E-GEOD-66281 | biostudies-arrayexpress
Project description:Function exhaustion and inefficient tumor infiltration rate limit NK cells based cancer immunotherapy. Even though the role of ADAR1 in immune cells and tumorigenesis is gradually gaining attention, its role on NK cells is elusive. In this study, we found ADAR1 expression level was upregulated in peripheral blood (PB)-NK cells from patients with melanoma. ADAR1 knockdown NK cells showed enhanced anti-tumor activity in vitro and in vivo. NK cells specific Adar1 deletion mice showed better tumor control and higher NK cells infiltration level. RNA-seq analysis revealed that NK shADAR1 cells exhibited an activation phenotype with highly cell migration potential. Higher tumor infiltration level of NK shADAR1 cells were verified in three-dimensional (3D) Matrigel-spheroid experiment. Mechanically, we also observed ADAR1 deficiency in NK cells accompanied by RIG-I signaling pathway inhibition and CD38 expression decline, resulting in higher cell mobility, proliferation, and tumor killing capacity. These data suggest ADAR1 may be an emerging therapeutic target for enhanced NK cell immunotherapy.
2026-06-03 | GSE275892 | GEO
Project description:CD73 is a metabolic immune checkpoint that regulates the homeostatic balance of adenosine levels in the tumor microenvironment (TME). However, the regulation of CD73 abnormal expression by Epstein-Barr virus (EBV) in EBV-associated malignancies and its immune editing mechanism on natural killer (NK) cells remains unclear. In this study, we demonstrate that CD73 is upregulated in EBV-associated malignancies and is negatively correlated with the anti-tumor activity of NK cells. Mechanistically, the EBV latent protein LMP2A upregulates CD73 expression through the PI3K/AKT signaling pathway, and the metabolic product of CD73, adenosine, negatively regulates the anti-tumor function of NK cells through multiple signaling pathways. Furthermore, targeted knockout of CD73, small molecule inhibitor, or neutralizing antibody combined with adoptive transfer of NK cells significantly improved the treatment efficacy for EBV-positive nasopharyngeal carcinoma (NPC). Importantly, we also found abnormal upregulation of CD73 in EBV-positive lymphoma, gastric cancer and lung cancer. In summary, our research identifies the mechanism of immune evasion of NK cell anti-tumor function in EBV-associated malignancies through the abnormal expression of CD73, and targeting CD73 combined with adoptive transfer of NK cells may provide a new strategy for immunotherapy of EBV-related malignancies.
2026-07-23 | GSE309453 | GEO
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:Elucidating the mechanisms by which immune cells become dysfunctional in tumors is critical to developing next-generation immunotherapies. We profiled proteomes of cancer cells, monocyte/macrophages, CD4+ and CD8+ T cells, and NK cells isolated from tumors, liver, and blood of 48 patients with hepatocellular carcinoma. We found that tumor macrophages induce the sphingosine-1-phospate-degrading enzyme SGPL1, which dampened their inflammatory phenotype and anti-tumor function in vivo. We further discovered that the signaling scaffold protein AFAP1L2, typically only found in activated NK cells, is also upregulated in chronically stimulated CD8+ T cells in tumors. Ablation of AFAP1L2 in CD8+ T cells increased their viability upon repeated stimulation and enhanced their antitumor activity synergistically with PD-L1 blockade in mouse models. Our data revealed new targets for immunotherapy and provide a resource on immune cell proteomes in liver cancer (www.immunomics.ch/liver).
2023-04-19 | PXD040957 | Pride
Project description:CD73 is a metabolic immune checkpoint that regulates the homeostatic balance of adenosine levels in the tumor microenvironment (TME). However, the regulation of CD73 abnormal expression by Epstein-Barr virus (EBV) in EBV-associated malignancies and its immune editing mechanism on natural killer (NK) cells remains unclear. In this study, we demonstrate that CD73 is upregulated in EBV-associated malignancies and is negatively correlated with the anti-tumor activity of NK cells. Mechanistically, the EBV latent protein LMP2A upregulates CD73 expression through the PI3K/AKT signaling pathway, and the metabolic product of CD73, adenosine, negatively regulates the anti-tumor function of NK cells through multiple signaling pathways. Furthermore, targeted knockout of CD73, small molecule inhibitor, or neutralizing antibody combined with adoptive transfer of NK cells significantly improved the treatment efficacy for EBV-positive nasopharyngeal carcinoma (NPC). Importantly, we also found abnormal upregulation of CD73 in EBV-positive lymphoma, gastric cancer and lung cancer. In summary, our research identifies the mechanism of immune evasion of NK cell anti-tumor function in EBV-associated malignancies through the abnormal expression of CD73, and targeting CD73 combined with adoptive transfer of NK cells may provide a new strategy for immunotherapy of EBV-related malignancies.
2026-07-23 | GSE309452 | GEO
Project description:Natural Killer (NK) cells are critical actors of the anti-tumoral immune response. However, NK cells are often dysfunctional in cancer patients, particularly in hematological malignancies like Acute Myeloid Leukemias (AML), where patients typically exhibit low NK cells numbers and activity. In addition, there is increasing interest in using allogenic NK cells transplantation as cancer immunotherapy. New strategies are however required to both reactivate NK cells in cancer patients and enhance the anti-tumor activity of transplanted NK cells. Here, we demonstrate that targeting SUMOylation, a protein post-translational modification, activates NK cells from both healthy donors and AML patients. Subasumstat (TAK-981), a first-in-class inhibitor of SUMOylation used in phase I/II clinical trials, enhances NK cells degranulation, secretion of inflammatory cytokines (IFN-γ, TNF-α, FasL) and cytotoxicity against AML cells. In vivo, TAK-981 improves the anti-leukemic efficacy of ex-vivo expanded cord-blood NK cells in leukemia-bearing mice. One early effect of TAK-981 is to specifically increase the accessibility and activation of cis-regulatory regions of interferon pathway genes and induce their transcription. TAK-981 induces the secretion of interferon-beta, mostly by NK cells and monocytes, which is required for NK cells activation. Surprisingly, IFNB1 induction is independent of MDA5, cGas, IRF-1, -3 and -7. Altogether, this suggests that targeting SUMOylation activates a non-canonical interferon pathway able to boost NK cells anti-leukemic potential.
2025-06-16 | GSE285061 | GEO
Project description:Natural Killer (NK) cells are critical actors of the anti-tumoral immune response. However, NK cells are often dysfunctional in cancer patients, particularly in hematological malignancies like Acute Myeloid Leukemias (AML), where patients typically exhibit low NK cells numbers and activity. In addition, there is increasing interest in using allogenic NK cells transplantation as cancer immunotherapy. New strategies are however required to both reactivate NK cells in cancer patients and enhance the anti-tumor activity of transplanted NK cells. Here, we demonstrate that targeting SUMOylation, a protein post-translational modification, activates NK cells from both healthy donors and AML patients. Subasumstat (TAK-981), a first-in-class inhibitor of SUMOylation used in phase I/II clinical trials, enhances NK cells degranulation, secretion of inflammatory cytokines (IFN-γ, TNF-α, FasL) and cytotoxicity against AML cells. In vivo, TAK-981 improves the anti-leukemic efficacy of ex-vivo expanded cord-blood NK cells in leukemia-bearing mice. One early effect of TAK-981 is to specifically increase the accessibility and activation of cis-regulatory regions of interferon pathway genes and induce their transcription. TAK-981 induces the secretion of interferon-beta, mostly by NK cells and monocytes, which is required for NK cells activation. Surprisingly, IFNB1 induction is independent of MDA5, cGas, IRF-1, -3 and -7. Altogether, this suggests that targeting SUMOylation activates a non-canonical interferon pathway able to boost NK cells anti-leukemic potential.
2025-06-18 | GSE263923 | GEO
Project description:Natural Killer (NK) cells are critical actors of the anti-tumoral immune response. However, NK cells are often dysfunctional in cancer patients, particularly in hematological malignancies like Acute Myeloid Leukemias (AML), where patients typically exhibit low NK cells numbers and activity. In addition, there is increasing interest in using allogenic NK cells transplantation as cancer immunotherapy. New strategies are however required to both reactivate NK cells in cancer patients and enhance the anti-tumor activity of transplanted NK cells. Here, we demonstrate that targeting SUMOylation, a protein post-translational modification, activates NK cells from both healthy donors and AML patients. Subasumstat (TAK-981), a first-in-class inhibitor of SUMOylation used in phase I/II clinical trials, enhances NK cells degranulation, secretion of inflammatory cytokines (IFN-γ, TNF-α, FasL) and cytotoxicity against AML cells. In vivo, TAK-981 improves the anti-leukemic efficacy of ex-vivo expanded cord-blood NK cells in leukemia-bearing mice. One early effect of TAK-981 is to specifically increase the accessibility and activation of cis-regulatory regions of interferon pathway genes and induce their transcription. TAK-981 induces the secretion of interferon-beta, mostly by NK cells and monocytes, which is required for NK cells activation. Surprisingly, IFNB1 induction is independent of MDA5, cGas, IRF-1, -3 and -7. Altogether, this suggests that targeting SUMOylation activates a non-canonical interferon pathway able to boost NK cells anti-leukemic potential.
2025-06-16 | GSE284887 | GEO