Similar Datasets
Project description:Glioblastoma (GBM) is an incurable cancer despite aggressive treatment paradigms. Current immunotherapies, such as CTLA-4 and/or PD-1 blockade, have yet to demonstrate benefits for GBM. A key barrier is the immunologically “cold” nature of GBM defined by insufficient tumor antigen presentation and lack of T cells infiltration. We previously demonstrated that pharmacologic inhibition of Protein Phosphatase-2A (PP2A), using a small molecule inhibitor, synergized with PD1 blockade in multiple preclinical tumor models including GBM. However, PP2A is ubiquitously expressed in many cell types and regulates many cellular pathways. The cell type or molecular mechanism responsible for PP2A-modulated tumor immunity is poorly understood. Here, we demonstrate that genetic ablation of PP2A in glioma cells sufficiently promotes tumor immunogenicity by enhancing 1) dsDNA production and thereby cGAS-Type I interferon (IFN) signaling, 2) MHC-I expression and 3) tumor mutational burden. PP2A deficient glioma enhances DC activation and cross presentation to promote clonal expansion of tumor antigen specific CD8 cells. PP2A deficiency also markedly sensitize tumors to immune checkpoint blockade and radiotherapy. Single cell analysis of murine glioma demonstrates that PP2A deficient tumors have 1) increased infiltration of CD8+ T cell, NK cell and cDC1 cells, 2) reduced infiltration of immunosuppressive tumor associated macrophages, 3) promotion of IFN signaling in both myeloid and tumor cells, and 4) reduced glioma-associated gene signature that predicts poor prognosis in glioma patients. This is the first study to establish a role for PP2A in regulating dsDNA-cGAS-STING signaling and collectively, our results suggest that PP2A is a promising novel target to enhance anti-tumor immunity for glioma.
2023-05-17 | GSE213308 | GEO
Project description:Glioblastoma (GBM) is an incurable cancer despite aggressive treatment paradigms. Current immunotherapies, such as CTLA-4 and/or PD-1 blockade, have yet to demonstrate benefits for GBM. A key barrier is the immunologically “cold” nature of GBM defined by insufficient tumor antigen presentation and lack of T cells infiltration. We previously demonstrated that pharmacologic inhibition of Protein Phosphatase-2A (PP2A), using a small molecule inhibitor, synergized with PD1 blockade in multiple preclinical tumor models including GBM. However, PP2A is ubiquitously expressed in many cell types and regulates many cellular pathways. The cell type or molecular mechanism responsible for PP2A-modulated tumor immunity is poorly understood. Here, we demonstrate that genetic ablation of PP2A in glioma cells sufficiently promotes tumor immunogenicity by enhancing 1) dsDNA production and thereby cGAS-Type I interferon (IFN) signaling, 2) MHC-I expression and 3) tumor mutational burden. PP2A deficient glioma enhances DC activation and cross presentation to promote clonal expansion of tumor antigen specific CD8 cells. PP2A deficiency also markedly sensitize tumors to immune checkpoint blockade and radiotherapy. Single cell analysis of murine glioma demonstrates that PP2A deficient tumors have 1) increased infiltration of CD8+ T cell, NK cell and cDC1 cells, 2) reduced infiltration of immunosuppressive tumor associated macrophages, 3) promotion of IFN signaling in both myeloid and tumor cells, and 4) reduced glioma-associated gene signature that predicts poor prognosis in glioma patients. This is the first study to establish a role for PP2A in regulating dsDNA-cGAS-STING signaling and collectively, our results suggest that PP2A is a promising novel target to enhance anti-tumor immunity for glioma.
2023-05-17 | GSE213307 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2023-02-09 | GSE199271 | GEO
Project description:STING-Type I interferon (IFN) signaling in myeloid cells plays a critical role in effective antitumor immune responses, but STING agonist as monotherapy has shown limited efficacy in clinical trials. The mechanisms that downregulate STING signaling are not fully understood. Here, we report that Protein phosphatase 2A (PP2A) with its specific B regulatory subunit STRN4 negatively regulated STING-Type I IFN in macrophages. Mice with macrophages PP2A deficiency exhibited reduced tumor progression. The tumor microenvironment showed decreased immunosuppressive and increased IFN-activated macrophages and CD8+ T cells. Mechanistically, we demonstrated that hippo kinase MST1/2 was required for STING activation. STING agonist induced dissociation of PP2A from MST1/2 in normal macrophages, but not in tumor conditioned macrophages. Furthermore, our data showed that STRN4 mediated PP2A binding to and dephosphorylation of hippo kinase MST1/2, resulting in stabilization of YAP/TAZ to antagonize STING activation. In human GBM patients, YAP/TAZ was highly expressed in tumor-associated macrophages but not in non-tumor macrophages. We also demonstrated that PP2A/STRN4 deficiency in macrophages reduced YAP/TAZ expression and sensitized tumor conditioned macrophages to STING stimulation. In summary, we demonstrated that PP2A/STRN4-YAP/TAZ is a previously unappreciated mechanism that mediate immunosuppression in tumor-associated macrophages and targeting PP2A/STRN4-YAP/TAZ axis can sensitize tumors to immunotherapy.
2023-02-09 | GSE199247 | GEO
Project description:STING-Type I interferon (IFN) signaling in myeloid cells plays a critical role in effective antitumor immune responses, but STING agonist as monotherapy has shown limited efficacy in clinical trials. The mechanisms that downregulate STING signaling are not fully understood. Here, we report that Protein phosphatase 2A (PP2A) with its specific B regulatory subunit STRN4 negatively regulated STING-Type I IFN in macrophages. Mice with macrophages PP2A deficiency exhibited reduced tumor progression. The tumor microenvironment showed decreased immunosuppressive and increased IFN-activated macrophages and CD8+ T cells. Mechanistically, we demonstrated that hippo kinase MST1/2 was required for STING activation. STING agonist induced dissociation of PP2A from MST1/2 in normal macrophages, but not in tumor conditioned macrophages. Furthermore, our data showed that STRN4 mediated PP2A binding to and dephosphorylation of hippo kinase MST1/2, resulting in stabilization of YAP/TAZ to antagonize STING activation. In human GBM patients, YAP/TAZ was highly expressed in tumor-associated macrophages but not in non-tumor macrophages. We also demonstrated that PP2A/STRN4 deficiency in macrophages reduced YAP/TAZ expression and sensitized tumor conditioned macrophages to STING stimulation. In summary, we demonstrated that PP2A/STRN4-YAP/TAZ is a previously unappreciated mechanism that mediate immunosuppression in tumor-associated macrophages and targeting PP2A/STRN4-YAP/TAZ axis can sensitize tumors to immunotherapy.
2023-02-09 | GSE199251 | GEO
Project description:Toxoplasma gondii is an important neurotropic pathogen that establishes latent infections in humans that can cause toxoplasmosis in immunocompromised individuals. It replicates inside host cells and has developed several strategies to manipulate host immune responses. However, the cytoplasmic pathogen-sensing pathway that detects T. gondii is not well-characterized. Here, we found that cyclic GMP-AMP synthase (cGAS), a sensor of foreign dsDNA, is required for activation of anti-T. gondii immune signaling in a mouse model. We also found that mice deficient in STING (Sting gt/gt mice) are much more susceptible to T. gondii infection than WT mice. Of note, the induction of inflammatory cytokines, type I IFNs, and interferon-stimulated genes in the spleen from Sting gt/gt mice was significantly impaired. Sting gt/gt mice exhibited more severe symptoms than cGAS-deficient mice after T. gondii infection. Interestingly, we found that the dense granule protein GRA15 from T. gondii is secreted into the host cell cytoplasm and then localizes to the endoplasmic reticulum, mediated by the second transmembrane motif in GRA15, which is essential for activating STING and innate immune responses. Mechanistically, GRA15 promoted STING polyubiquitination at Lys-337 and STING oligomerization in a TRAF protein-dependent manner. Accordingly, GRA15-deficient T. gondii failed to elicit robust innate immune responses compared with WT T. gondii. Consequently, GRA15-/- T. gondii was more virulent and caused higher mortality of WT mice but not Sting gt/gt mice upon infection. Together, T. gondii infection triggers cGAS/STING signaling, which is enhanced by GRA15 in a STING- and TRAF-dependent manner.
| S-EPMC6851339 | biostudies-literature
Project description:Chronic activation of inflammatory pathways and suppressed interferon are hallmarks of immunosuppressive tumors. Previous studies have shown that CD11b integrin agonists could enhance anti-tumor immunity through myeloid reprograming, but the underlying mechanisms remain unclear. Herein we find that CD11b agonists alter tumor-associated macrophage (TAM) phenotypes by repressing NF-κB signaling and activating interferon gene expression simultaneously. Repression of NF-κB signaling involves degradation of p65 protein and is context independent. In contrast, CD11b agonism induces STING/STAT1 pathway-mediated interferon gene expression through FAK-mediated mitochondrial dysfunction, with the magnitude of induction dependent on the tumor microenvironment and amplified by cytotoxic therapies. Using tissues from phase I clinical studies, we demonstrate that GB1275 treatment activates STING and STAT1 signaling in TAMs in human tumors. These findings suggest potential mechanism-based therapeutic strategies for CD11b agonists and identify patient populations more likely to benefit.
2023-03-21 | GSE220959 | GEO
Project description:BackgroundAs one of the most common malignancy, lung adenocarcinoma (LUAD) is characterized by low 5-year survival rate. This research aimed to investigate the effects of ribonucleotide reductase regulatory subunit M2 (RRM2) on malignant biological behaviors and activation of cGAS/STING pathway. We also explored the synergistic sensitization mechanisms of RRM2 and radiotherapy.MethodsBioinformatic tools were used to evaluate the clinical significance of RRM2 in LUAD patients. The roles of RRM2 in malignant phenotype and DNA damage in LUAD cells were investigated with cell proliferation, colony formation, immunofluorescence, modified Boyden chamber and comet assays. The mouse models were used to evaluate the biological significance of RRM2 in vivo. Cytotoxic T cell infiltration was evaluated via flow cytometric analysis and immunohistochemistry staining in C57BL/6 mice. We also explored the synergistic effects of RRM2 silencing and radiation on LUAD cells with apoptosis assay and immunoblotting in vitro.ResultsBioinformatic analysis revealed that RRM2 had diagnostic values for LUAD patients. Higher levels of RRM2 predicted worse prognosis. RRM2 silencing inhibited LUAD cell proliferation, invasion and migration. RRM2 knockdown induced S phase arrest and DNA damage. RRM2 silencing induced cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway, and the downstream targets were regulated in a STING-dependent manner. Knockdown of RRM2 suppressed tumor growth in the xenograft tumor models. RRM2 deficiency increased CD8 + T cells in the tumor tissues and spleens. Furthermore, RRM2 silencing had synergistic effects with radiation on inhibiting cell proliferation and promoting apoptosis. Meanwhile, this combination promoted the activation of cGAS/STING signaling pathway synergistically, and simultaneously increased expression of IFNβ, CCL5 and CXCL10.ConclusionOur results demonstrated that RRM2 silencing had anti-tumor values and activated the cGAS/STING signaling pathway. RRM2 silencing increased CD8 + T cells infiltration. RRM2 silencing cooperated with radiation to inhibit LUAD cell proliferation, promote apoptosis and enhance the activation of cGAS/STING signaling pathway. RRM2 could be a promising target for tumor regression through cancer immunotherapy in LUAD.
| S-EPMC8051110 | biostudies-literature
Project description:Background & aimsPancreatic ductal adenocarcinoma (PDA) is a lethal chemoresistant cancer that exhibits early metastatic spread. The highly immunosuppressive PDA tumor microenvironment renders patients resistant to emerging immune-targeted therapies. Building from our prior work, we evaluated stimulator of interferon genes (STING) agonist activation of PDA cell interferon-α/β-receptor (IFNAR) signaling in systemic antitumor immune responses.MethodsPDA cells were implanted subcutaneously to wild-type, IFNAR-, or CXCR3-knockout mice. Tumor growth was monitored, and immune responses were comprehensively profiled.ResultsHuman and mouse STING agonist ADU-S100 reduced local and distal tumor burden and activated systemic antitumor immune responses in PDA-bearing mice. Effector T-cell infiltration and inflammatory cytokine and chemokine production, including IFN-dependent CXCR3-agonist chemokines, were elevated, whereas suppressive immune populations were decreased in treated tumors. Intratumoral STING agonist treatment also generated inflammation in distal noninjected tumors and peripheral immune tissues. STING agonist treatment of type I IFN-responsive PDA tumors engrafted to IFNAR-/- recipient mice was sufficient to contract tumors and stimulate local and systemic T-cell activation. Tumor regression and CD8+ T-cell infiltration were abolished in PDA engrafted to CXCR3-/- mice treated with STING agonist.ConclusionsThese data indicate that STING agonists promote T-cell infiltration and counteract immune suppression in locally treated and distant tumors. Tumor-intrinsic type I IFN signaling initiated systemic STING-mediated antitumor inflammation and required CXCR3 expression. STING-mediated induction of systemic immune responses provides an approach to harness the immune system to treat primary and disseminated pancreatic cancers.
| S-EPMC8081932 | biostudies-literature
Project description:With short survival time, glioblastoma (GBM) is the most malignant tumor in the central nervous system. Recently, epigenetic enzymes play essential roles in the regulation of tumorigenesis and cancer development of GBM. However, little is known about MYST1/KAT8/MOF, a histone acetylation enzyme, in GBM. The present study shows that MYST1 promotes GBM progression through activating epidermal growth factor receptor (EGFR) signaling. MYST1 expression was increased in GBM and was negatively correlated with prognosis in patients with glioma and GBM. Knockdown of MYST1 reduced cell proliferation and BrdU incorporation in LN229, U87, and A172 GBM cells. Besides, MYST1 downregulation also induced cell cycle arrest at G2M phase, as well as the reduced expression of CDK1, Cyclin A, Cyclin B1, and increased expression of p21CIP1/Waf1 . Meanwhile, Self-renewal capability in vitro and tumorigenecity in vivo were also impaired after MYST1 knockdown. Importantly, MYST1 expression was lowly expressed in mesenchymal subtype of GBM and was positively correlated with EGFR expression in a cohort from The Cancer Genome Atlas. Western blot subsequently confirmed that phosphorylation and activation of p-Try1068 of EGFR, p-Ser473 of AKT and p-Thr202/Tyr204 of Erk1/2 were also decreased by MYST1 knockdown. Consistent with the results above, overexpression of MYST1 promoted GBM growth and activated EGFR signaling in vitro and in vivo. In addition, erlotinib, a US Food and Drug Administration approved cancer drug which targets EGFR, was able to rescue MYST1-promoted cell proliferation and EGFR signaling pathway. Furthermore, the transcription of EGF, an EFGR ligand, was shown to be positively regulated by MYST1 possibly via H4K16 acetylation. Our findings elucidate MYST1 as a tumor promoter in GBM and an EGFR activator, and may be a potential drug target for GBM treatment.
| S-EPMC6912028 | biostudies-literature