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PP2Ac/STRN4 negatively regulates STING-Type I interferon signaling in tumor associated macrophages

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE199271 | GEO | 2023/02/09

REPOSITORIES: GEO

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PP2Ac/STRN4 negatively regulates STING-Type I interferon signaling in tumor associated macrophages [RNA-Seq]

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

PP2Ac/STRN4 negatively regulates STING-Type I interferon signaling in tumor associated macrophages [scRNA-seq]

2023-02-09 | GSE199247 | GEO

PP2Ac Deficiency Enhances Tumor Immunogenicity by Activating STING-Type I Interferon Signaling in Glioblastoma

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-05-17 | GSE213309 | GEO

PP2Ac Deficiency Enhances Tumor Immunogenicity by Activating STING-Type I Interferon Signaling in Glioblastoma [scRNA]

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

PP2Ac Deficiency Enhances Tumor Immunogenicity by Activating STING-Type I Interferon Signaling in Glioblastoma [RNA]

2023-05-17 | GSE213307 | GEO