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

Abstract

Glioblastoma (GBM) is an immunologically “cold” tumor that does not respond to current immunotherapy. Here, we demonstrate a fundamental role for the α-isoform of the catalytic subunit of protein phosphatase-2A (PP2Ac) in regulating glioma immunogenicity. Genetic ablation of PP2Ac in glioma cells enhanced double stranded DNA (dsDNA) production and cGAS-type I interferon (IFN) signaling, MHC-I expression, and tumor mutational burden. In co-culture experiments, PP2Ac deficiency in glioma cells promoted dendritic cell (DC) cross presentation and clonal expansion of CD8+ T cells. In vivo, PP2Ac depletion sensitized tumors to immune checkpoint blockade and radiotherapy treatment. Single cell analysis demonstrated that PP2Ac deficiency increased CD8+ T cell, NK cell, and DC accumulation and reduced immunosuppressive tumor associated macrophages. Furthermore, loss of PP2Ac increased IFN signaling in myeloid and tumor cells and reduced expression of a tumor gene signature associated with worse patient survival in TCGA. Collectively, this study establishes a novel role for PP2Ac in inhibiting dsDNA-cGAS-STING signaling to suppress anti-tumor immunity in glioma.

The phosphatase inhibitor LB-100 creates neoantigens in colon cancer cells through perturbation of mRNA splicing

“…For example, it was shown that ablation of PP2A in regulatory T cells (Tregs) inhibits their immunosuppressive activity and causes auto-immunity (Apostolidis et al, 2016 ). Moreover, LB-100 in glioma activates the cGAS-STING pathway, leading to the activation of interferon signaling and an increase in CD8+ killer T-cell proliferation (Ho et al, 2023 ; Mondal et al, 2023 ). The role of PP2A inhibition in increased T-cell proliferation has also been observed by others (Zhou et al, 2014 ).…”

Emerging mechanisms and implications of cGAS-STING signaling in cancer immunotherapy strategies

“…Additionally, the disruption of protein phosphatase 2A catalytic subunit (PP2Ac) in glioblastoma cells enhances dsDNA production and cGAS-IFN-α/β signaling. This process increases MHC-I expression, decreases immunosuppressive TAMs, and sensitizes tumors to immune checkpoint blockade and radiotherapy 64 . Ho et al 65 have found that, in TAMs, protein PP2A and its specific B regulatory subunit Striatin 4 (STRN4) negatively regulate STING-dependent IFN-α/β production.…”

Glioma–Immune Cell Crosstalk in Tumor Progression

“…In general, tumors may reduce MHC-I antigen expression through genomic defects perturbing heavy a-chain (i.e., HLA-encoded) or light chain (i.e., B2-microglobulin, B2M) gene expression or transcriptional (e.g., downregulation of type I and II IFN pathways, loss of transcriptional regulators, DNA hypermethylation or histone deacetylases) and post-transcriptional (e.g., microRNAs) silencing [128]. While the exact mechanisms underlying MHC-I downregulation in gliomas remain to be elucidated, a recent paper by Mondal et al identified an intimate relationship between type I IFN signaling and MHC-I expression in glioma [129]. Specifically, they found that inhibition of tumor-expressed protein phosphatase-2A (PP2A), a serine-threonine phosphatase involved in DNA damage response and inhibition of which had previously been shown to enhance tumor immunity [130,131], leads to the accumulation of cytosolic double-stranded DNA and consequent induction of the cGAS-STING pathway.…”

“…Other promising avenues of regulating cytokine levels in the TME include modulating intracellular pathways involved in immune suppression. For example, studies have shown that PP2A inhibition or activation of the STING pathway increases type I IFN signaling in TAMs, leading to increased activation of macrophages and CD8+ T cells and a subsequent reduction in tumor volume in mice [129,157].…”