Protein Phosphatase 2A Inactivation Induces Microsatellite Instability, Neoantigen Production and Immune Response

Overview

Journal Nat Commun

Specialty Biology

Date 2021 Dec 16

PMID 34911954

Citations 21

Authors

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

Shih-Chieh Hung

Affiliations

Soon will be listed here.

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.

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