# Regulation of Tumor Immunogenicity in Glioblastoma

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2023 · $455,315

## Abstract

PROJECT SUMMARY
Glioblastoma (GBM) is the most common primary malignant brain tumor in adults that is universally fatal
despite multimodal treatment. Novel therapies are therefore critically needed. Immunotherapy, such as
checkpoint blockade, has thus far failed to demonstrate clinical efficacy. GBM has high intrinsic resistance to
antitumor immunity due to, among other factors, low expression of MHC-I and lack of T-cell infiltration.
Strategies to promote immunogenicity of GBM to sensitize tumor to checkpoint therapy is needed. Protein
phosphatase 2A (PP2A) is a ubiquitous serine/threonine phosphatase comprised of a catalytic (C), regulatory (B)
and scaffolding (A) subunit. We have previously reported that pharmacological inhibition of PP2Ac can enhance
the efficacy of anti-PD1 blockade in multiple preclinical models, including GBM. However, the mechanism(s) or
cell type(s) responsible for the enhanced antitumor immune response is not well understood. Recently, we found
that deficiency of PP2Ac, by genetic modification, in glioma cells resulted in enhanced interferon signaling, which
is essential to eliciting antitumor immune response. PP2A deficiency in glioma cells enhanced MHC-I expression,
tumor T-cell infiltration and sensitivity to checkpoint blockade in vivo. We also demonstrated that PP2Ac
deficiency led to enhanced production of cytoplasmic double-stranded DNA (dsDNA), which is known to activate
cGAS-STING signaling, a potent simulator of interferon production. Moreover, from unbiased screening of all
known regulatory B subunits, we identified PPP2R2C, a specific B subunit of PP2A, to have a similar role as
PP2Ac in promoting MHC-I expression. In this project, we will first elucidate the effect of PP2Ac deficiency in
glioma cells on the immunological landscape of the tumor microenvironment and will identify the immune cell
types responsible for PP2Ac modulated antitumor immunity. We will then dissect the molecular mechanisms
that link PP2A deficiency to cGAS-STING activation and promotion of interferon signaling in the glioma
microenvironment. We will also identify the role of the specific regulatory B subunit, PPP2R2C, in modulating
dsDNA production and cGAS-STING signaling. Finally, we will investigate the ability of PP2Ac deficiency to
enhance the therapeutic efficacy of radiation therapy, a major component of current standard-of-care and a
known stimulator of cGAS-STING signaling. The immediate goal of this project is to identify the mechanisms of
PP2A modulated immunogenicity in GBM, with the long-term goal of developing precise PP2A targeting
strategies to increase effectiveness of immunotherapies for GBM. We believe this study fits the mission of NINDS
to seek fundamental knowledge of the nervous system and to use that knowledge to reduce the burden of
neurological disease such as brain tumor.

## Key facts

- **NIH application ID:** 10638755
- **Project number:** 1R01NS131545-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Sze Chun Winson Ho
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $455,315
- **Award type:** 1
- **Project period:** 2023-04-01 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10638755

## Citation

> US National Institutes of Health, RePORTER application 10638755, Regulation of Tumor Immunogenicity in Glioblastoma (1R01NS131545-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10638755. Licensed CC0.

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