ARID1A deficiency promotes mutability and potentiates therapeutic antitumor immunity unleashed by immune checkpoint blockade

Jianfeng Shen, Zhenlin Ju, Wei Zhao, Lulu Wang, Yang Peng, Zhongqi Ge, Zachary D. Nagel, Jun Zou, Chen Wang, Prabodh Kapoor, Xiangyi Ma, Ding Ma, Jiyong Liang, Shumei Song, Jinsong Liu, Leona D. Samson, Jaffer A. Ajani, Guo Min Li, Han Liang, Xuetong ShenGordon B. Mills, Guang Peng

    Research output: Contribution to journalArticle

    85 Scopus citations

    Abstract

    ARID1A (the AT-rich interaction domain 1A, also known as BAF250a) is one of the most commonly mutated genes in cancer 1,2 . The majority of ARID1A mutations are inactivating mutations and lead to loss of ARID1A expression 3 , which makes ARID1A a poor therapeutic target. Therefore, it is of clinical importance to identify molecular consequences of ARID1A deficiency that create therapeutic vulnerabilities in ARID1A-mutant tumors. In a proteomic screen, we found that ARID1A interacts with mismatch repair (MMR) protein MSH2. ARID1A recruited MSH2 to chromatin during DNA replication and promoted MMR. Conversely, ARID1A inactivation compromised MMR and increased mutagenesis. ARID1A deficiency correlated with microsatellite instability genomic signature and a predominant C>T mutation pattern and increased mutation load across multiple human cancer types. Tumors formed by an ARID1A-deficient ovarian cancer cell line in syngeneic mice displayed increased mutation load, elevated numbers of tumor-infiltrating lymphocytes, and PD-L1 expression. Notably, treatment with anti-PD-L1 antibody reduced tumor burden and prolonged survival of mice bearing ARID1A-deficient but not ARID1A-wild-type ovarian tumors. Together, these results suggest ARID1A deficiency contributes to impaired MMR and mutator phenotype in cancer, and may cooperate with immune checkpoint blockade therapy.

    Original languageEnglish (US)
    Pages (from-to)556-562
    Number of pages7
    JournalNature medicine
    Volume24
    Issue number5
    DOIs
    StatePublished - May 1 2018

    ASJC Scopus subject areas

    • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    Shen, J., Ju, Z., Zhao, W., Wang, L., Peng, Y., Ge, Z., Nagel, Z. D., Zou, J., Wang, C., Kapoor, P., Ma, X., Ma, D., Liang, J., Song, S., Liu, J., Samson, L. D., Ajani, J. A., Li, G. M., Liang, H., ... Peng, G. (2018). ARID1A deficiency promotes mutability and potentiates therapeutic antitumor immunity unleashed by immune checkpoint blockade. Nature medicine, 24(5), 556-562. https://doi.org/10.1038/s41591-018-0012-z