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

Yu-Ting Yen, May Chien, Pei-Yi Wu, Chi-Chang Ho, Chun-Te Ho, Kevin Chih-Yang Huang, Shu-Fen Chiang, K. S. Clifford Chao, William Tzu-Liang Chen and Shih-Chieh Hung ()
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Yu-Ting Yen: China Medical University
May Chien: China Medical University
Pei-Yi Wu: China Medical University
Chi-Chang Ho: China Medical University
Chun-Te Ho: China Medical University
Kevin Chih-Yang Huang: China Medical University
Shu-Fen Chiang: China Medical University
K. S. Clifford Chao: China Medical University
William Tzu-Liang Chen: China Medical University
Shih-Chieh Hung: China Medical University

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract Microsatellite-instable (MSI), a predictive biomarker for immune checkpoint blockade (ICB) response, is caused by mismatch repair deficiency (MMRd) that occurs through genetic or epigenetic silencing of MMR genes. Here, we report a mechanism of MMRd and demonstrate that protein phosphatase 2A (PP2A) deletion or inactivation converts cold microsatellite-stable (MSS) into MSI tumours through two orthogonal pathways: (i) by increasing retinoblastoma protein phosphorylation that leads to E2F and DNMT3A/3B expression with subsequent DNA methylation, and (ii) by increasing histone deacetylase (HDAC)2 phosphorylation that subsequently decreases H3K9ac levels and histone acetylation, which induces epigenetic silencing of MLH1. In mouse models of MSS and MSI colorectal cancers, triple-negative breast cancer and pancreatic cancer, PP2A inhibition triggers neoantigen production, cytotoxic T cell infiltration and ICB sensitization. Human cancer cell lines and tissue array effectively confirm these signaling pathways. These data indicate the dual involvement of PP2A inactivation in silencing MLH1 and inducing MSI.

Date: 2021
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DOI: 10.1038/s41467-021-27620-x

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