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: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: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.
2025-06-16 | GSE284887 | 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:Tumor resistance to immune cells remains a major obstacle for successful treatment. NK cells are emerging tools for cancer therapy. However, due to differential and subset-specific expression of inhibitory NK cell receptors, often only subsets of NK cells exert reactivity against particular cancer types. Using a genome-wide CRISPR/Cas9 knockout (KO) screen in melanoma, we revealed resistance factors against NK cell attack and evaluated their differential impact on NK cell subpopulations. We show that melanoma cells deficient in antigen-presenting machinery or the IFNγ signaling pathway displayed enhanced sensitivity to NK cell killing. Treatment with IFNγ induced melanoma cell resistance that depended on B2M required for both classical and non-classical MHC-I expression. HLA-E mediated melanoma cell resistance to NKG2A+ KIR-, and partially to NKG2A+ KIR+ NK cells. Treatment of NK cells with the NKG2A blocking monalizumab resulted in enhanced NK cell reactivity to similar extent as deletion of HLA-E in melanoma cells. The combination of monalizumab with lirilumab, blocking KIR2 receptors, together with DX9, an anti-KIR3DL1 mAb, was required to restore the response of all NK cells against IFNγ-pretreated tumor cells of different origins. Our data reveal insights into NK cell subset reactivity and strategies how to leverage their full anti-tumor potential.
2024-07-10 | GSE261626 | GEO
Project description:The surface receptor CD8a is present on 20-80% of human (but not mouse) NK cells, yet its function on NK cells remains poorly understood. CD8a expression on donor NK cells was associated with a lack of therapeutic responses for leukemia patients in prior studies, thus we hypothesized that CD8a may impact critical NK cell functions. Here, we discovered that CD8a- NK cells had improved control of leukemia in xenograft models, compared to CD8a+ NK cells, likely due to an enhanced capacity for proliferation. Unexpectedly, CD8a expression was induced on approximately 30% of previously CD8a- NK cells following IL-15 stimulation. These ‘induced’ CD8a+ (‘iCD8a+’) NK cells had the greatest proliferation, responses to IL-15 signaling, and metabolic activity, compared to those that sustained existing CD8a expression (‘sustained CD8a+) or those that remained CD8a- (‘persistent CD8a-‘). These iCD8a+ cells originated from an IL-15Rb high NK cell population, with CD8a expression dependent on the transcription factor RUNX3. Moreover, CD8A CRISPR/Cas9 deletion resulted in enhanced responses through the activating receptor NKp30, possibly by modulating KIR inhibitory function. Thus, CD8a status identifies human NK cell capacity for IL-15-induced proliferation and metabolism in a time-dependent fashion and exhibits a suppressive effect on NK cell activating receptors
2024-06-20 | GSE263686 | GEO
Project description:Background. Although several immunotherapies against glioblastoma (GBM) have been investigated for long time, only limited effective results are acquired. Therefore, we developed immunotherapy based on genome edited NK cells knocking out the checkpoint receptor, which would overcome the immunosuppressive tumor microenvironment in GBM. Methods. We generated T cell immunoglobulin and ITIM domain (TIGIT), an inhibitory receptor expressed on lymphocytes, knockout (KO) human primary NK cells using the clustered regularly interspaced short palindromic repeats (CRISPR)/ CRISPR-associated protein9 (Cas9), each single guide RNA targeting different genome sites on TIGIT coding exons. To detect anti-tumor activity of genome edited NK cells against GBM, we utilized 2D adherent model and spheroids derived from GBM cell lines, U87, T98G, LN18, and U251. Subsequently, we performed real time cell growth assays, flow cytometry based apoptosis assays, and ELISA for investigating anti-tumor activity. Result. We established TIGIT KO human primary NK cells using CRISPR/Cas9. Flow cytometry indicated effective knockout of TIGIT and unchanged expression of immune checkpoint receptors other than TIGIT. T7 endonuclease I mutation detection assays showed that RNPs disrupted the intended genome sites. Using real time cell growth assays, we revealed enhanced anti-tumor activity of genome edited NK cells against 2D adherent GBM cells. The genome edited NK cells also exhibits enhanced anti-tumor effect against GBM spheroids derived from GBM cell lines.Conclusion. Our founding suggests that immunotherapy based on TIGIT KO NK cells using CRISPR/Cas9 is a promising therapy against GBM.
2022-09-11 | GSE212941 | GEO