Protein phosphatase 2A inactivation induces microsatellite instability, neoantigen production and immune response

Yen, Yu‐Ting; Chien, May B.; Wu, Pei-Shan; Ho, Chi-Chang; Ho, Chun‐Te; Huang, Kevin Chih-Yang; Chiang, Shu‐Fen; Chao, K.; Chen, William Tzu-Liang; Hung, Shih‐Chieh

doi:10.1038/s41467-021-27620-x

Cited by 36 publications

(33 citation statements)

References 68 publications

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“… 302 , 303 Inhibition of PP2A with LB-100 has been reported to synergize with PD-1 to enhance the reactivity of microstatellite instability colon cancer to immunotherapy. 304 …”

Section: Progress In Innovative Pharmacological Approaches That Targe...mentioning

confidence: 99%

Targeting protein phosphatases for the treatment of inflammation-related diseases: From signaling to therapy

Pan

Zhou

Zhang

et al. 2022

Sig Transduct Target Ther

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Inflammation is the common pathological basis of autoimmune diseases, metabolic diseases, malignant tumors, and other major chronic diseases. Inflammation plays an important role in tissue homeostasis. On one hand, inflammation can sense changes in the tissue environment, induce imbalance of tissue homeostasis, and cause tissue damage. On the other hand, inflammation can also initiate tissue damage repair and maintain normal tissue function by resolving injury and restoring homeostasis. These opposing functions emphasize the significance of accurate regulation of inflammatory homeostasis to ameliorate inflammation-related diseases. Potential mechanisms involve protein phosphorylation modifications by kinases and phosphatases, which have a crucial role in inflammatory homeostasis. The mechanisms by which many kinases resolve inflammation have been well reviewed, whereas a systematic summary of the functions of protein phosphatases in regulating inflammatory homeostasis is lacking. The molecular knowledge of protein phosphatases, and especially the unique biochemical traits of each family member, will be of critical importance for developing drugs that target phosphatases. Here, we provide a comprehensive summary of the structure, the “double-edged sword” function, and the extensive signaling pathways of all protein phosphatases in inflammation-related diseases, as well as their potential inhibitors or activators that can be used in therapeutic interventions in preclinical or clinical trials. We provide an integrated perspective on the current understanding of all the protein phosphatases associated with inflammation-related diseases, with the aim of facilitating the development of drugs that target protein phosphatases for the treatment of inflammation-related diseases.

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“… 302 , 303 Inhibition of PP2A with LB-100 has been reported to synergize with PD-1 to enhance the reactivity of microstatellite instability colon cancer to immunotherapy. 304 …”

Section: Progress In Innovative Pharmacological Approaches That Targe...mentioning

confidence: 99%

Targeting protein phosphatases for the treatment of inflammation-related diseases: From signaling to therapy

Pan

Zhou

Zhang

et al. 2022

Sig Transduct Target Ther

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“…Mutations in either gene lead to high-frequency microsatellite instability (MSI) 54 . Yen et al 25 found that deletion of the Ppp2r1a gene, which encodes PP2A-A, in murine Lgr5 + intestinal crypt cells in vitro leads to MMR-deficient genetic signatures and positive MSI assay results. These findings have been corroborated in humans: CRC data from The Cancer Genome Atlas Project has revealed that MSI is associated with diminished mRNA and protein levels of PPP2R1A 25 .…”

Section: Lb100: a Modulator Of Immunotherapymentioning

confidence: 99%

“…Yen et al 25 found that deletion of the Ppp2r1a gene, which encodes PP2A-A, in murine Lgr5 + intestinal crypt cells in vitro leads to MMR-deficient genetic signatures and positive MSI assay results. These findings have been corroborated in humans: CRC data from The Cancer Genome Atlas Project has revealed that MSI is associated with diminished mRNA and protein levels of PPP2R1A 25 . These data suggest that PP2A plays a role in maintaining normal MMR, and aberrant regulation of PP2A is associated with MSI.…”

Section: Lb100: a Modulator Of Immunotherapymentioning

confidence: 99%

“…To clarify the mechanism triggering MSI, Yen et al 25 examined the histology of mice bearing syngeneic CT26 CRC tumors and found that PP2A-deficient mice show more tumor-infiltrating cytotoxic T cells than PP2A-wildtype mice. They hypothesized that Ppp2r1a knockdown converts microsatellite stable “cold” tumors that escape immune recognition to MSI “hot” tumors that attract immune cells by increasing tumor neoantigen expression 25 . To this end, the authors identified 270 missense transcripts, corresponding to 220 genes, shared by 3 PP2A-deleted tumor samples but not found in any PP2A-wildtype tumor samples 25 , 55 .…”

Section: Lb100: a Modulator Of Immunotherapymentioning

confidence: 99%

“…They hypothesized that Ppp2r1a knockdown converts microsatellite stable “cold” tumors that escape immune recognition to MSI “hot” tumors that attract immune cells by increasing tumor neoantigen expression 25 . To this end, the authors identified 270 missense transcripts, corresponding to 220 genes, shared by 3 PP2A-deleted tumor samples but not found in any PP2A-wildtype tumor samples 25 , 55 . These results suggest that PP2A inhibition increases genetic errors in cancer cells via MSI, increased tumor neoantigens, and subsequent cytotoxic T cell attraction in CRC 25 .…”

Section: Lb100: a Modulator Of Immunotherapymentioning

confidence: 99%

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Targeting PP2A for cancer therapeutic modulation

et al. 2022

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Protein phosphatases play essential roles as negative regulators of kinases and signaling cascades involved in cytoskeletal organization. Protein phosphatase 2A (PP2A) is highly conserved and is the predominant serine/threonine phosphatase in the nervous system, constituting more than 70% of all neuronal phosphatases. PP2A is involved in diverse regulatory functions, including cell cycle progression, apoptosis, and DNA repair. Although PP2A has historically been identified as a tumor suppressor, inhibition of PP2A has paradoxically demonstrated potential as a therapeutic target for various cancers. LB100, a water-soluble, small-molecule competitive inhibitor of PP2A, has shown particular promise as a chemo- and radio-sensitizing agent. Preclinical success has led to a profusion of clinical trials on LB100 adjuvant therapies, including a phase I trial in extensive-stage small-cell lung cancer, a phase I/II trial in myelodysplastic syndrome, a phase II trial in recurrent glioblastoma, and a completed phase I trial assessing the safety of LB100 and docetaxel in various relapsed solid tumors. Herein, we review the development of LB100, the role of PP2A in cancer biology, and recent advances in targeting PP2A inhibition in immunotherapy.

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A combination of protein phosphatase 2A inhibition and checkpoint immunotherapy: a perfect storm

Clark,

Lu,

et al. 2024

Molecular Oncology

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Immune checkpoint blockade has emerged as a potent new tool in the war on cancer. However, only a subset of cancer patients benefit from this therapeutic modality, sparking a search for combination therapies to increase the fraction of responding patients. We argue here that inhibition of protein phosphatase 2A (PP2A) is a promising approach to increase responses to immune checkpoint blockade and other therapies that rely on the presence of tumor‐reactive T cells. Inhibition of PP2A increases neoantigen expression on tumor cells, activates the cGAS/STING pathway, suppresses regulatory T cells, and increases cytotoxic T cell activation. In preclinical models, inhibition of PP2A synergizes with immune checkpoint blockade and emerging evidence indicates that patients who have tumors with mutations in PP2A respond better to immune checkpoint blockade. Therefore, inhibition of PP2A activity may be an effective way to sensitize cancer cells to immune checkpoint blockade and cell‐based therapies using tumor‐reactive T cells.

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Protein phosphatase 2A inactivation induces microsatellite instability, neoantigen production and immune response

Cited by 36 publications

References 68 publications

Targeting protein phosphatases for the treatment of inflammation-related diseases: From signaling to therapy

Targeting protein phosphatases for the treatment of inflammation-related diseases: From signaling to therapy

Targeting PP2A for cancer therapeutic modulation

A combination of protein phosphatase 2A inhibition and checkpoint immunotherapy: a perfect storm

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