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Project description:Deletion of the mRNA endonuclease Regnase-1 promotes NK cell anti-tumor activity via OCT2- dependent transcription of Ifng
| PRJNA996077 | ENA
Project description:Cytokine-inducible SH2-containing protein (CIS; encoded by the gene CISH) is a key negative regulator of interleukin-15 (IL-15) signaling in natural killer (NK) cells. Here, we develop human CISH-knockout (CISH-/-) NK cells using an induced pluripotent stem cell-derived NK cell (iPSC-NK cell) platform. CISH-/- iPSC-NK cells demonstrate increased IL-15-mediated JAK-STAT signaling activity. Consequently, CISH-/- iPSC-NK cells exhibit improved expansion and increased cytotoxic activity against multiple tumor cell lines when maintained at low cytokine concentrations. CISH-/- iPSC-NK cells display significantly increased in vivo persistence and inhibition of tumor progression in a leukemia xenograft model. Mechanistically, CISH-/- iPSC-NK cells display improved metabolic fitness characterized by increased basal glycolysis, glycolytic capacity, maximal mitochondrial respiration, ATP-linked respiration, and spare respiration capacity mediated by mammalian target of rapamycin (mTOR) signaling that directly contributes to enhanced NK cell function. Together, these studies demonstrate that CIS plays a key role to regulate human NK cell metabolic activity and thereby modulate anti-tumor activity.
| S-EPMC7415618 | biostudies-literature
Project description:A major challenge in natural killer (NK) cell immunotherapy is the limited persistence of NK cells in vivo. However, the proliferation of NK cells is dependent on cytokines such as interleukin-2 (IL-2). Although IL-2 is a critical cytokine for NK cell activation and survival, IL-2 administration in adoptive NK cell therapy can induce adverse toxicities. To improve the persistence of NK cells and attenuate the systemic toxicity of IL-2, we constructed a cell-restricted artificial IL-2, named membrane-bound IL-2 (mbIL-2), comprising human IL-2 and human IL-2Rα joined by a classic linker. We found that mbIL-2-activated NK-92 cells can survive and proliferate in vitro and in vivo, independent of exogenous IL-2, while mbIL-2-expressing NK-92 cells do not support bystander cell survival or proliferation. Additionally, mbIL-2 enhanced NK-92 cell-mediated antitumor activity by tuning the IL-2 receptor downstream signals and NK cell receptor repertoire expression. To conclude, our novel mbIL-2 improves NK-92 cell persistence and enhances NK-92 cell-mediated antitumor activity. NK-92 cells genetically modified to express the novel mbIL-2 with potential significance for clinical development.
| S-EPMC9519007 | biostudies-literature
Project description:We previously reported that deletion of Foxo1, via Ncr1-iCre mice from the expression of NKp46 onward, led to enhanced natural killer (NK) cell maturation and effector function. In this model, however, the role of Foxo1 in regulating NK cell specification and early development remains exclusive. Herein, we utilized a murine model of hematopoietic-specific deletion of Foxo1 before lymphoid specification, by crossing mice carrying floxed Foxo1 alleles (Foxo1 fl/fl) with Vav1-iCre mice, to revisit the role of Foxo1 on NK cell specification and early development. The data showed that hematopoietic-specific deletion of Foxo1 resulted in increased proportion and numbers of common lymphoid progenitors (CLP) (Lin-CD127+c-Kit+Sca-1+), pre-pro NK b cells (Lin-Sca-1+c-Kit-CD135-CD127+), as well as committed Lin-CD122+ cells and CD3-CD19-NKp46+ NK cells in bone marrow. Hematopoietic-specific deletion of Foxo1 also promoted NK cells proliferation in a cell-intrinsic manner, indicated by increased Ki-67 expression and more expansion of NK cell after ex vivo stimulation with IL-15. The reason for Foxo1 suppressing NK cell proliferation might be its direct transcription of the cell-cycle inhibitory genes, such as p21 cip1, p27 kip1, p130, Gadd45a, and Ccng2 (cyclin G2) in NK cells, supported by the evidence of decreased mRNA expression of p21 cip1, p27 kip1, p130, Gadd45a, and Ccng2 in Foxo1-deficient NK cells and direct binding of Foxo1 on their promoter region. Furthermore, hematopoietic-specific deletion of Foxo1 resulted in increased ratio of mature NK subsets, such as CD11b+CD27- and CD43+KLRG1+ NK cells, but decreased ratio of immature NK subsets, such as CD27+CD11b- and CD27+CD11b+ NK cells, consistent with the findings in the murine model of Ncr1-iCre mediated Foxo1 deletion. Conclusively, Foxo1 not only acts as a negative checkpoint on NK cell maturation, but also represses NK cell specification and proliferation. The relative higher expression of Foxo1 in CLP and early NK precursors may also contribute to the later NK cell proliferation and responsiveness, which warranties another separate study in the future.
| S-EPMC6519137 | biostudies-literature
Project description:Inflammasomes are molecular complexes that trigger an inflammatory response upon detection of pathogens or danger signals. Recent studies suggest that they are also involved in cancer progression. However, their roles during tumorigenesis remain poorly understood and controversial. Here, we investigated whether inflammasome activation supports mammary tumor growth. Using mouse models of invasive breast cancer, our results demonstrate that the absence of a functional inflammasome impairs tumor growth. Importantly, tumors implanted into inflammasome-deficient mice recruited significantly less neutrophils and more natural killer (NK) cells, and these latter cells displayed a more active phenotype. Interestingly, NK cell depletion abolished the anti-tumoral effect observed in inflammasome-deficient mice, although inflammasome-regulated cytokine neutralization had no effect. Thus, our work identifies a novel role for the inflammasome in supporting mammary tumor growth by attenuating NK cell recruitment and activity. These results suggest that inflammasome inhibition could be a putative target for treating invasive breast cancers.
| S-EPMC7526436 | biostudies-literature
Project description:We isolated splenic NK cells and cultured them for 3 days in 100 ng/ml IL-15. Next, we stimulated the cells with plate-bound anti-NK1.1 for 6 hours and sorted YFP+ (IFNg+) and YFP- (IFNg-) populations. We then performed gene expression profiling analysis using data obtained from RNA-seq from unstimulated, YFP+ or YFP- NK cells.
2023-08-01 | GSE227863 | GEO
Project description:Ginsenosides are the principal active components of ginseng and are considered attractive candidates for combination cancer therapy because they can kill tumors and have favorable safety profiles. However, the overall benefit of ginsenosides remains unclear, particularly in cancer immunosurveillance, considering the controversial results showing repression or promotion of immune responses. Here we identify a potentiating role of ginsenoside F1 (G-F1) in cancer surveillance by natural killer (NK) cells. Among 15 different ginsenosides, G-F1 most potently enhanced NK cell cytotoxicity in response to diverse activating receptors and cancer cells. G-F1 also improved cancer surveillance in mouse models of lymphoma clearance and metastatic melanoma that rely on NK cell activity. G-F1-treated NK cells exhibited elevated cytotoxic potential such as upregulation of cytotoxic mediators and of activation signals upon stimulation. NK cell potentiation by G-F1 was antagonized by insulin-like growth factor (IGF)-1 blockade and recapitulated by IGF-1 treatment, suggesting the involvement of IGF-1. Thus, our results suggest that G-F1 enhances NK cell function and may have chemotherapeutic potential in NK cell-based immunotherapy. We anticipate our results to be a starting point for further comprehensive studies of ginsenosides in the immune cells mediating cancer surveillance and the development of putative therapeutics.
| S-EPMC6279892 | biostudies-literature
Project description:Here we investigated the potential immune-enhancing activity of Isodon japonicus on murine splenocyte and natural-killer (NK) cells in vitro. The ethanol extract of I. japonicus significantly enhanced the proliferation of splenocyte and induced the significant enhancement of NK cells' activity against tumor cells (YAC-1). In addition, I. japonicus increased the production of interferon (IFN)-? and tumor necrosis factor (TNF)-?, suggesting that the increase in NK cell cytotoxicity could be due to the enhancement of the NK cell production of both cytokines. Taken together, I. japonicus extract inhibited the growth of human leukemia cells (K562) by 74%. Our observation indicated that the anti-tumor effects of I. japonicus may be attributed to its ability to serve as a stimulant of NK anti-tumor activity. In addition, our results support the development of functional food studies on I. japonicus.
| S-EPMC3344252 | biostudies-literature
Project description:BackgroundRibonucleases (RNases) play central roles in the post-transcriptional regulation of mRNA stability. Our preliminary results revealed that the endonuclease Regnase-1 is specifically upregulated in osteoarthritic chondrocytes. We herein explored the possible functions and regulatory mechanisms of Regnase-1 in a mouse model of osteoarthritis (OA).MethodsThe expression and target genes of Regnase-1 were identified by microarray analysis in primary-culture mouse articular chondrocytes. Experimental OA in mice was induced by destabilization of the medial meniscus (DMM). The function of Regnase-1 in DMM-induced post-traumatic OA mice was examined by adenovirus-mediated overexpression or knockdown in knee joint tissues, and also by using Regnase-1 heterozygous knockout mice (Zc3h12a+/-).ResultsAmong the RNases, Regnase-1 was exclusively upregulated in chondrocytes stimulated with OA-associated catabolic factors. Adenovirus-mediated overexpression or knockdown of Regnase-1 alone in joint tissues did not cause OA-like changes. However, overexpression of Regnase-1 in joint tissues significantly ameliorated DMM-induced post-traumatic OA cartilage destruction, whereas knockdown or genetic ablation of Regnase-1 exacerbated DMM-induced cartilage destruction. Mechanistic studies suggested that Regnase-1 suppresses cartilage destruction by modulating the expression of matrix-degrading enzymes in chondrocytes.ConclusionOur results collectively suggest that upregulated Regnase-1 in OA chondrocytes may function as a chondro-protective effector molecule during OA pathogenesis by forming a negative feedback loop of catabolic signals, such as matrix-degrading enzyme expression, in OA chondrocytes.
| S-EPMC8045248 | biostudies-literature
Project description:Therapy induced senescence (TIS) in tumors and TIS cancer cells secrete proinflammatory senescence-associated secretory phenotype (SASP) factors. SASP factors promote TIS cancer cells to re-enter the growth cycle with stemness characteristics, resulting in chemo-resistance and disease relapse. Herein, we show that the immunotherapeutic HCW9218, comprising transforming growth factor-β (TGF-β) receptor II and interleukin (IL)-15/IL-15 receptor α domains, enhances metabolic and cytotoxic activities of immune cells and reduces TIS tumor cells in vivo to improve the efficacy of docetaxel and gemcitabine plus nab-paclitaxel against B16F10 melanoma and SW1990 pancreatic tumors, respectively. Mechanistically, HCW9218 treatment reduces the immunosuppressive tumor microenvironment and enhances immune cell infiltration and cytotoxicity in the tumors to eliminate TIS cancer cells. Immuno-depletion analysis suggests that HCW9218-activated natural killer cells play a pivotal role in TIS cancer cell removal. HCW9218 treatment following docetaxel chemotherapy further enhances efficacy of tumor antigen-specific and anti-programmed death-ligand 1 (PD-L1) antibodies in B16F10 tumor-bearing mice. We also show that HCW9218 treatment decreases TIS cells and lowers SASP factors in off-target tissues caused by chemotherapy of tumor-bearing mice. Collectively, HCW9218 has the potential to significantly enhance anti-tumor efficacy of chemotherapy, therapeutic antibodies, and checkpoint blockade by eliminating TIS cancer cells while reducing TIS-mediated proinflammatory side effects in normal tissues.
| S-EPMC8899672 | biostudies-literature