ARID1A deficiency promotes mutability and potentiates therapeutic antitumor immunity unleashed by immune checkpoint blockade
Open accessAbstract
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.
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Mutations in SWI-SNF chromatin remodeling complex genes may sensitize human tumors to ICIs, and epigenetic modulators can potentiate ICI response by increasing chemokines that recruit CD8+ T cells.
“Several studies have demonstrated that mutations in genes involved in the SWI-SNF chromatin remodeling complex may sensitize human tumors to ICIs and that treatment with an epigenetic modulator can potentiate the ICI-mediated antitumor response through increased production of chemokines responsible for recruiting CD8 + T cells (104-107).”
From Immune Checkpoint Inhibitors for the Treatment of Cancer: Clinical Impact and Mechanisms of Response and Resistance (2021) · cites this paper as [104]
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Self-citation
- Authors
- 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., Shen, X., Mills, G. B., & Peng, G.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Massachusetts Institute of Technology (US)
- Tongji Hospital (CN)
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Peng, Guang
- ORCID
- Venue
- Nature Medicine
- Published
- 2018-05
- Volume
- 24
- Issue
- 5
- Pages
- 556-562
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC6076433
- OpenAlex
- W2802645166
- Cited by
- 562
- References
- 35
- Citations by year
- 2026: 35 · 2025: 69 · 2024: 75 · 2023: 91 · 2022: 83 · 2021: 74 · 2020: 75 · 2019: 50 · 2018: 9
- FWCI
- 18.58
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Defense
- Cancer Research Institute
- Cancer Prevention and Research Institute of Texas
- National Institutes of Health
- National Cancer Institute (P30CA016672, P01CA092584, R01CA181663)
- National Institute of General Medical Sciences (R01GM093104)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Keywords
- ARID1A, DNA mismatch repair, MSH2, microsatellite instability, mutational load, immune checkpoint blockade, PD-L1 blockade, tumor-infiltrating lymphocytes, PD-L1 expression, ovarian cancer, chromatin recruitment, DNA replication, cancer immunotherapy
- MeSH terms
- Animals, DNA-Binding Proteins, Female, Humans, Immunotherapy, Mice, Inbred C57BL, Mutation, Neoplasms, Nuclear Proteins, Protein Binding, Transcription Factors, Lymphocytes, Tumor-Infiltrating, Cell Line, Tumor, MutS Homolog 2 Protein, DNA Mismatch Repair
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