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| Status |
Public on May 17, 2023 |
| Title |
PP2Ac Deficiency Enhances Tumor Immunogenicity by Activating STING-Type I Interferon Signaling in Glioblastoma [RNA] |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
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.
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| Overall design |
We implanted subcutanous or intracranial SB28 murine glioma in WT and LysMcrePP2Acfl/fl mice. 18 days after implantation, tumor tissue was harvested, and single cell suspensions were obtained and sent for sequencing.
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| Web link |
https://doi.org/10.6084/m9.figshare.21094390
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| Contributor(s) |
Oishika D, Isha M, Beisi X, Rongze L, Winson H |
| Citation(s) |
37219874 |
| NIH grant(s) |
| Grant ID |
Grant title |
Affiliation |
Name |
| R01 NS131545 |
Regulation of Tumor Immunogenicity in Glioblastoma |
University of California San Francisco |
Sze Chun Winson Ho |
| R01 NS126501 |
Regulation of Macrophage- and Microglia-mediated STING Signaling in Glioblastoma |
University of California San Francisco |
Rongze Olivia Lu |
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| |
| Submission date |
Sep 13, 2022 |
| Last update date |
Aug 18, 2023 |
| Contact name |
Beisi Xu |
| E-mail(s) |
beisi.xu@stjude.org
|
| Organization name |
St Jude Children's Research Hosipital
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| Department |
Center for Applied Bioinformatics
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| Street address |
262 Danny Thomas Pl
|
| City |
Memphis |
| State/province |
Tennessee |
| ZIP/Postal code |
38105 |
| Country |
USA |
| |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (6)
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| This SubSeries is part of SuperSeries: |
| GSE213309 |
PP2Ac Deficiency Enhances Tumor Immunogenicity by Activating STING-Type I Interferon Signaling in Glioblastoma |
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| Relations |
| BioProject |
PRJNA880423 |
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