ARID1A deficiency impairs mismatch repair to increase tumor mutation load and promote tumor progression.

  • Major finding:ARID1A deficiency impairs mismatch repair to increase tumor mutation load and promote tumor progression.

  • Mechanism: ARID1A binds to the mismatch repair protein MSH2, recruiting it to chromatin during replication.

  • Impact:ARID1A deficiency may confer sensitivity to immune checkpoint blockade in patients with cancer.

ARID1A is a component of the SWI/SNF chromatin remodeling complex and is frequently subject to inactivating mutations in cancer. Shen and colleagues sought to identify therapeutic vulnerabilities generated by ARID1A deficiency. A proteomics screen found that ARID1A interacts with the mismatch repair (MMR) protein MSH2, facilitating the recruitment of MSH2 to chromatin during replication. Consistent with this finding, ARID1A deficiency impaired MMR, as did depletion of the SWI/SNF catalytic subunit BRG1, suggesting that chromatin remodeling activity may be required for MMR. Moreover, MMR capacity correlated with ARID1A expression in a panel of 21 ovarian cancer cell lines. Cells with ARID1A depletion exhibited an increased mutation frequency, consistent with an MMR deficiency. Data from The Cancer Genome Atlas revealed that ARID1A mutations are associated with a high mutation load in human tumors, and ARID1A mutations were highly enriched in patients with tumors exhibiting microsatellite instability. It has been reported that the increased neoantigen load and tumor-infiltrating lymphocytes (TIL) in MMR-deficient tumors may render them more susceptible to immune checkpoint blockade. Thus, the association between ARID1A deficiency and MMR deficiency suggested that ARID1A mutations might confer sensitivity to immune checkpoint blockade. In ovarian cancer mouse models, ARID1A depletion increased tumor progression, mutation rate, TILs, and immune checkpoint activation. Consequently, these tumors were more sensitive to treatment with an anti–PD-L1 antibody than ARID1A-proficient tumors, exhibiting reduced tumor growth and extended survival. In addition to demonstrating that ARID1A deficiency impairs MMR, these findings demonstrate that ARID1A-deficient tumors may be sensitive to immune checkpoint blockade, suggesting the potential for ARID1A status as a predictive biomarker of response.

Shen J Ju Z, Zhao W, Wang L, Peng Y, Ge Z, et al. ARID1A deficiency promotes mutability and potentiates therapeutic antitumor immunity unleashed by immune checkpoint blockade. Nature Med 2018 May 7 [Epub ahead of print].

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