Jagged2 targeting in lung cancer activates anti-tumor immunity via Notch-induced functional reprogramming of tumor-associated macrophages
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE227671 | GEO | 2024/04/17
REPOSITORIES: GEO
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Project description:Signaling through Notch receptors intrinsically regulates tumor cell development and growth. However, whether Notch ligands on cancer cells impact anti-tumor immunity remains unclear. We demonstrate that deletion of Notch ligand Jagged2, but not Jagged1, in lung cancer cells attenuates tumor growth and activates anti-tumor T cell responses. Jagged2 deletion in cancer cells incites intra-tumor accumulation of macrophages with elevated capacity to uptake, process, and present antigens. Also, transfer of Jagged2KO tumors-related macrophages into mice provokes lymphocyte-mediated anti-tumor actions, while macrophage ablation in mice restores Jagged2KO tumor growth. Jagged2 deletion on lung tumors induces Notch ligands DLL1/4, which signal through Notch1-2 on macrophages to stimulate IRF4-driven anti-tumor responses. Intercepting DLL1/4 in tumors or IRF4 in myeloid cells blunts macrophage expansion and reinstates Jagged2KO tumor growth. Therapeutically, anti-Jagged2 treatments restrict tumor growth and augment immunotherapy effectiveness. Findings elucidate how cancer cell Jagged2 promotes immune-evasion and identify Jagged2-targeting immunotherapy to activate anti-tumor immunity.
2024-04-17 | GSE228105 | GEO
Project description:Notch expressed on CD4+ T cells transduces signals that mediate their effector functions and survival by interacting with Notch ligands on adjacent cells. Although Notch signaling is known to be cis-inhibited by Notch ligands expressed on the same cells, the role of Notch ligands on T cells remain unclear. In this report we demonstrate that the Notch ligand Dll1 on CD4+ T cells transduces signals required for the maintenance of activated CD4+ T cells without affecting Notch signaling in the same cells. T cell-specific Dll1-deficient (Dll1-/-) mice did not show any defect in T cell development in thymus or spleen. Co-transfer of CD4+ T cells from Dll1-/- and control mice into recipient mice followed by immunization revealed a rapid decline of CD4+ T cells from Dll1-/- mice compared with control cells. Dll1-/- mice exhibited lower clinical scores of experimental autoimmune encephalitis than control mice. The expression of Notch target genes in CD4+ T cells from Dll1-/- mice was not affected, suggesting that Dll1 deficiency in T cells does not affect cis Notch signaling. Overexpression of the intracellular domain of Dll1 in Dll1-deficient CD4+ T cells partially rescued impaired survival. Our data highlight Dll1 as an independent regulator of Notch-signaling for the survival of activated CD4+ T cells, and provide new insight into the physiological roles of Notch ligands as well as a regulatory mechanism important for maintaining adaptive immune responses The mRNA expression in activated CD4+ T cells from mouse was obtained by DNA microarray analysis. These mRNA expression was compared.
2016-01-09 | E-GEOD-76693 | biostudies-arrayexpress
Project description:Notch expressed on CD4+ T cells transduces signals that mediate their effector functions and survival by interacting with Notch ligands on adjacent cells. Although Notch signaling is known to be cis-inhibited by Notch ligands expressed on the same cells, the role of Notch ligands on T cells remain unclear. In this report we demonstrate that the Notch ligand Dll1 on CD4+ T cells transduces signals required for the maintenance of activated CD4+ T cells without affecting Notch signaling in the same cells. T cell-specific Dll1-deficient (Dll1-/-) mice did not show any defect in T cell development in thymus or spleen. Co-transfer of CD4+ T cells from Dll1-/- and control mice into recipient mice followed by immunization revealed a rapid decline of CD4+ T cells from Dll1-/- mice compared with control cells. Dll1-/- mice exhibited lower clinical scores of experimental autoimmune encephalitis than control mice. The expression of Notch target genes in CD4+ T cells from Dll1-/- mice was not affected, suggesting that Dll1 deficiency in T cells does not affect cis Notch signaling. Overexpression of the intracellular domain of Dll1 in Dll1-deficient CD4+ T cells partially rescued impaired survival. Our data highlight Dll1 as an independent regulator of Notch-signaling for the survival of activated CD4+ T cells, and provide new insight into the physiological roles of Notch ligands as well as a regulatory mechanism important for maintaining adaptive immune responses
2016-01-09 | GSE76693 | GEO
Project description:BACKGROUND: The Notch signaling pathway is an evolutionary conserved signal transduction pathway involved in embryonic patterning and regulation of cell fates during development and self-renewal. Recent studies have demonstrated that this pathway is integral to a complex system of interactions, involving as well other signal transduction pathways, and implicated in distinct human diseases. Delta-like 1 (Dll1) is one of the known ligands of the Notch receptors. The role of the Notch ligands is less well understood. Loss-of-function of Dll1 leads to embryonic lethality, but reduction of Delta-like 1 protein levels has not been studied in adult stage. METHODOLOGY/PRINCIPAL FINDINGS: Here we present the haploinsufficient phenotype of Dll1 and a missense mutant Dll1 allele (Dll1(C413Y)). Haploinsufficiency leads to a complex phenotype with several biological processes altered. These alterations reveal the importance of Dll1 mainly in metabolism, energy balance and in immunology. The animals are smaller, lighter, with altered fat to lean ratio and have increased blood pressure and a slight bradycardia. The animals have reduced cholesterol and triglyceride levels in blood. At the immunological level a subtle phenotype is observed due to the effect and fine-tuning of the signaling network at the different levels of differentiation, proliferation and function of lymphocytes. Moreover, the importance of the proteolytic regulation of the Notch signaling network emphasized. CONCLUSIONS/SIGNIFICANCE: In conclusion, slight alterations in one player of Notch signaling alter the entire organism, emphasizing the fine-tuning character of this pathway in a high number of processes. Four organs (liver, spleen, thymus, brain) of the Dll1 mutant mouse line analysed by cDNA microarray technology. Experiments include four biological replicates for reference (wildtype) and mutant animals. Two technical replicates for each mutant mouse were performed. As reference pooled RNA of the same organ was used. 50% of the chip hybridisations are dye sway experiments.
2009-03-01 | E-GEOD-12954 | biostudies-arrayexpress
Project description:BACKGROUND: The Notch signaling pathway is an evolutionary conserved signal transduction pathway involved in embryonic patterning and regulation of cell fates during development and self-renewal. Recent studies have demonstrated that this pathway is integral to a complex system of interactions, involving as well other signal transduction pathways, and implicated in distinct human diseases. Delta-like 1 (Dll1) is one of the known ligands of the Notch receptors. The role of the Notch ligands is less well understood. Loss-of-function of Dll1 leads to embryonic lethality, but reduction of Delta-like 1 protein levels has not been studied in adult stage. METHODOLOGY/PRINCIPAL FINDINGS: Here we present the haploinsufficient phenotype of Dll1 and a missense mutant Dll1 allele (Dll1(C413Y)). Haploinsufficiency leads to a complex phenotype with several biological processes altered. These alterations reveal the importance of Dll1 mainly in metabolism, energy balance and in immunology. The animals are smaller, lighter, with altered fat to lean ratio and have increased blood pressure and a slight bradycardia. The animals have reduced cholesterol and triglyceride levels in blood. At the immunological level a subtle phenotype is observed due to the effect and fine-tuning of the signaling network at the different levels of differentiation, proliferation and function of lymphocytes. Moreover, the importance of the proteolytic regulation of the Notch signaling network emphasized. CONCLUSIONS/SIGNIFICANCE: In conclusion, slight alterations in one player of Notch signaling alter the entire organism, emphasizing the fine-tuning character of this pathway in a high number of processes.
2009-03-01 | GSE12954 | GEO
Project description:The most critical stage in initiation of melanoma metastasis is the radial to vertical growth transition, yet the triggers of this transition remain elusive. We introduce a novel perspective, suggesting that the microenvironment drives melanoma metastasis independently of mutation acquisition. Here we examined the changes in microenvironment that occur during melanoma radial growth. We show that direct contact of melanoma cells with the remote epidermal layer triggers vertical invasion via Notch signaling activation, the latter serving to inhibit MITF function. Briefly, within the native Notch ligand-free microenvironment, MITF, the melanocyte lineage master regulator, binds and represses miR-222/221 promoter in an RBPJK-dependent manner. However, when radial growth brings melanoma cells into contact with distal differentiated keratinocytes that express Notch ligands, the activated Notch intracellular domain impairs MITF binding to miR-222/221 promoter. This de-repression of miR-222/221 expression triggers initiation of invasion. Our findings may direct novel prevention opportunities via targeting specific microenvironment. Two replicates of Notch-activated cells that were seeded on Delta-like-1 (DLL1) (2 ng/µl ) coated plates were compared to two replicates of cells without Notch activation. The goal of this experiment is to evaluate the changes of miRs expression in melanoma cells upon Notch signaling activation.
2015-07-30 | E-GEOD-69403 | biostudies-arrayexpress
Project description:Tumor associated macrophages (TAMs) are known to play a role in a multitude of processes that facilitate lung cancer growth, including the suppression of tumoricidal immune activation and the absorption of chemotherapeutics. Therefore, deciphering new therapies to reprogram TAMs towards an anti-tumor phenotype is at the cutting-edge of therapy development. The presence of iron-loaded macrophages has been associated with a better prognosis in lung cancer patients. Iron accumulation in macrophages stimulates pro-tumoricidal macrophage activity that triggers cytotoxic T-cell responses in the tumor microenvironment. In this study, we propose super-paramagnetic iron oxide nanoparticles (SPIONs) as a promising anti-lung cancer adjuvant therapy to reduce tumor cell growth. We used SPIONs to target iron to macrophages and observed that SPION-loaded macrophages reduced tumor cell growth due to the oxidative stress. Additionally, we found that SPIONs completely rewire the tumor microenvironment in mice towards an anti-tumor state and that in combination with crizotinib, a lung cancer targeted therapy, SPIONs show an additive effect in decelerating tumor growth
2024-04-18 | PXD040145 | Pride
Project description:Objective DLL1 is a mammalian Notch ligand with essential functions during embryonic development. We tagged endogenous DLL1 in one homologous recombination step such that AcGFP-HA tagged DLL1 could be converted by Cre-mediated site-specific recombination into StrepFlag tagged DLL1. We anticipated that this should allow us to visualise DLL1 in living cells as well as allow for sorting and enrichment of DLL1-expressing cells and efficient purification of DLL1 protein complex. Results We generated constructs to express a DLL1 variant that carried C-terminal in frame an AcGFPHA tag flanked by loxP sites followed by a StrepFlag tag out of frame. Cre-mediated recombination removed AcGFP-HA and added StrepFlag in frame to DLL1. The AcGFPHAstopStrepFlag tag was added to the Dll1 cDNA to allow for tests in cultured cells in vitro and was introduced into endogenous DLL1 in mice using ES cells modified by homologous recombination. Tagged DLL1 protein was detected by antibodies against GFP and HA or Flag, respectively, both in CHO cell and embryo lysates. In CHO cells the AcGFP protein fused to DLL1 was functional. In vivo AcGFP expression was below the level of detection by direct fluorescence. However, the StrepFlag tag allowed us to specifically purify DLL1 complexes from embryo lysates. Homozygous mice expressing AcGFPHA or StrepFlag-tagged DLL1 revealed a vertebral column phenotype reminiscent of disturbances in AP polarity during somitogenesis, a process most sensitive to reduced DLL1 function. Thus, even small C-terminal tags can impinge on sensitive developmental processes requiring DLL1 activity.
2021-11-03 | PXD024680 | Pride
Project description:The gene expression profile of vaginal cells isolated from MRKHS patients, compared with those without MRKHS, presented alterations of developmental genes such as HOXB family, the Notch ligands JAG1 and DLL1 and MUC1, which can represent key elements in the pathogenesis of MRKHS, thus suggesting a potential alteration of networks involved in the formation of the female reproductive tract.
2013-11-22 | GSE52609 | GEO
Project description:Cancer cells rely on ATP-citrate lyase (Acly)-derived acetyl-CoA for lipid biogenesis and proliferation, marking Acly as promising therapeutic target. However, inhibitors may have side effects on tumor-associated macrophages (TAMs). TAMs are innate immune cells abundant in the tumor microenvironment (TME) and play central roles in tumorigenesis, progression and therapy response. Since macrophage Acly deletion was previously shown to elicit macrophages with a potential anti-tumor phenotype in vivo, we hypothesized that Acly targeting may elicit anti-tumor responses in macrophages, whilst inhibiting cancer cell proliferation. Here, we used a myeloid-specific knockout model to validate that absence of Acly decreases IL-4-induced macrophage activation. Using two distinct tumor models, we demonstrate that Acly deletion slightly alters tumor immune composition and TAM phenotype in a tumor type-dependent manner without affecting tumor growth. Together, our results indicate that targeting Acly in macrophages does not have detrimental effects on myeloid cells.
2021-06-30 | GSE169187 | GEO