Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

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

Abstract

ARID1A (the AT-rich interaction domain 1A, also known as BAF250a) is one of the most commonly mutated genes in cancer1,2. The majority of ARID1A mutations are inactivating mutations and lead to loss of ARID1A expression3, 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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: ARID1A interacts with MSH2.
Fig. 2: ARID1A deficiency promotes mutability through regulating MMR.
Fig. 3: ARID1A deficiency is associated with a MMR-defective mutator phenotype.
Fig. 4: ARID1A-deficient tumors display increased TILs, activation of immune checkpoint, and sensitization to immune checkpoint blockade therapy.

Similar content being viewed by others

References

  1. Wilson, B. G. & Roberts, C. W. SWI/SNF nucleosome remodellers and cancer. Nat. Rev. Cancer 11, 481–492 (2011).

    Article  CAS  Google Scholar 

  2. Wu, J. N. & Roberts, C. W. ARID1A mutations in cancer: another epigenetic tumor suppressor? Cancer Discov. 3, 35–43 (2013).

    Article  CAS  Google Scholar 

  3. Wu, R. C., Wang, T. L. & Shih, Ie. M. The emerging roles of ARID1A in tumor suppression. Cancer Biol. Ther. 15, 655–664 (2014).

    Article  Google Scholar 

  4. Wang, X. et al. Expression of p270 (ARID1A), a component of human SWI/SNF complexes, in human tumors. Int. J. Cancer 112, 636 (2004).

    Article  CAS  Google Scholar 

  5. Wang, X. et al. Two related ARID family proteins are alternative subunits of human SWI/SNF complexes. Biochem. J. 383, 319–325 (2004).

    Article  CAS  Google Scholar 

  6. Nagel, Z. D. et al. Multiplexed DNA repair assays for multiple lesions and multiple doses via transcription inhibition and transcriptional mutagenesis. Proc. Natl. Acad. Sci. USA 111, E1823–E1832 (2014).

    Article  CAS  Google Scholar 

  7. Mathur, R. et al. ARID1A loss impairs enhancer-mediated gene regulation and drives colon cancer in mice. Nat. Genet. 49, 296–302 (2017).

    Article  CAS  Google Scholar 

  8. Kandoth, C. et al. Mutational landscape and significance across 12 major cancer types. Nature 502, 333–339 (2013).

    Article  CAS  Google Scholar 

  9. Hause, R. J., Pritchard, C. C., Shendure, J. & Salipante, S. J. Classification and characterization of microsatellite instability across 18 cancer types. Nat. Med. 22, 1342–1350 (2016).

    Article  CAS  Google Scholar 

  10. Kane, M. F. et al. Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair-defective human tumor cell lines. Cancer Res. 57, 808–811 (1997).

    CAS  PubMed  Google Scholar 

  11. Zhao, H. et al. Mismatch repair deficiency endows tumors with a unique mutation signature and sensitivity to DNA double-strand breaks. eLife 3, e02725 (2014).

    Article  Google Scholar 

  12. Le, D. T. et al. PD-1 blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. 372, 2509–2520 (2015).

    Article  CAS  Google Scholar 

  13. Llosa, N. J. et al. The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints. Cancer Discov. 5, 43–51 (2015).

    Article  CAS  Google Scholar 

  14. Le, D. T. et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 357, 409–413 (2017).

    Article  CAS  Google Scholar 

  15. Tscharke, D. C., Croft, N. P., Doherty, P. C. & La Gruta, N. L. Sizing up the key determinants of the CD8(+) T cell response. Nat. Rev. Immunol. 15, 705–716 (2015).

    Article  CAS  Google Scholar 

  16. Pardoll, D. M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12, 252–264 (2012).

    Article  CAS  Google Scholar 

  17. Angelova, M. et al. Characterization of the immunophenotypes and antigenomes of colorectal cancers reveals distinct tumor escape mechanisms and novel targets for immunotherapy. Genome Biol. 16, 64 (2015).

    Article  Google Scholar 

  18. Bindea, G. et al. Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer. Immunity 39, 782–795 (2013).

    Article  CAS  Google Scholar 

  19. West, N. R. et al. Tumor-infiltrating lymphocytes predict response to anthracycline-based chemotherapy in estrogen receptor-negative breast cancer. BCR 13, R126 (2011).

    Article  CAS  Google Scholar 

  20. Allo, G. et al. ARID1A loss correlates with mismatch repair deficiency and intact p53 expression in high-grade endometrial carcinomas. Mod. Pathol. 27, 255–261 (2014).

    Article  CAS  Google Scholar 

  21. Chou, A. et al. Loss of ARID1A expression in colorectal carcinoma is strongly associated with mismatch repair deficiency. Hum. Pathol. 45, 1697–1703 (2014).

    Article  CAS  Google Scholar 

  22. Kim, M. S., Je, E. M., Yoo, N. J. & Lee, S. H. Loss of ARID1A expression is uncommon in gastric, colorectal, and prostate cancers. APMIS 120, 1020–1022 (2012).

    Article  Google Scholar 

  23. Wang, K. et al. Exome sequencing identifies frequent mutation of ARID1A in molecular subtypes of gastric cancer. Nat. Genet. 43, 1219–1223 (2011).

    Article  CAS  Google Scholar 

  24. Koster, B. D., de Gruijl, T. D. & van den Eertwegh, A. J. Recent developments and future challenges in immune checkpoint inhibitory cancer treatment. Curr. Opin. Oncol. 27, 482–488 (2015).

    Article  CAS  Google Scholar 

  25. Khalil, D. N., Smith, E. L., Brentjens, R. J. & Wolchok, J. D. The future of cancer treatment: immunomodulation, CARs and combination immunotherapy. Nat. Rev. Clin. Oncol. 13, 273–290 (2016).

    Article  CAS  Google Scholar 

  26. Pan, D. et al. A major chromatin regulator determines resistance of tumor cells to T cell-mediated killing. Science 359, 770–775 (2018).

    Article  CAS  Google Scholar 

  27. Miao, D. et al. Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma. Science 359, 801–806 (2018).

    Article  CAS  Google Scholar 

  28. Romano, P. et al. Cell Line Data Base: structure and recent improvements towards molecular authentication of human cell lines. Nucleic Acids Res. 37, D925–D932 (2009).

    Article  CAS  Google Scholar 

  29. Li, F. et al. The histone mark H3K36me3 regulates human DNA mismatch repair through its interaction with MutSα. Cell 153, 590–600 (2013).

    Article  CAS  Google Scholar 

  30. Herbst, R. S. et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515, 563–567 (2014).

    Article  CAS  Google Scholar 

  31. Peng, D. et al. Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy. Nature 527, 249–253 (2015).

    Article  CAS  Google Scholar 

  32. Li, H. et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics 25, 2078–2079 (2009).

    Article  Google Scholar 

  33. Van der Auwera, G. A. et al. From FastQ data to high confidence variant calls: the Genome Analysis Toolkit best practices pipeline. Curr. Protoc. Bioinformatics 43, 1–33 (2013).

    Google Scholar 

  34. Cibulskis, K. et al. Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples. Nat. Biotechnol. 31, 213–219 (2013).

    Article  CAS  Google Scholar 

  35. Cingolani, P. et al. A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3. Fly (Austin) 6, 80–92 (2012).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This research was supported by NCI Cancer Center Support Grant CA016672 to The University of Texas MD Anderson Cancer Center, Department of Defense grant OC140431, NIH R01 grant CA181663 to G.P., Cancer Prevention and Research Institute of Texas grant RP160242 to X.S. and G.P., NIH R01 grant GM093104 to X.S, and NIH P01 grant CA092584 to Z.D.N.

Author information

Authors and Affiliations

Authors

Contributions

J.S. and G.P. conceived the study. G.B.M. and G.P. designed experiments. J.S., L.W., and Y.P. performed experiments. Z.J., W.Z., Z.G., and H.L. performed bioinformatics analyses. J.S., Z.D.N., and L.D.S developed the MMR reporter assay. J.Z., C.W., X.M., D.M., and J. Liu contributed to ovarian tumor pathological analyses. S.S., J.A.A., P.K., J. Liang, G.-M.L., and X.S. contributed to the discussion of results. J.S. and G.P. wrote the manuscript. All authors participated in manuscript preparation and approved the final version of the manuscript.

Corresponding author

Correspondence to Guang Peng.

Ethics declarations

Competing interests

G.B.M. has received sponsored research support from Abbvie, AstraZeneca, Critical Outcomes Technology, Horizon Diagnostics, Illumina, Immunomet, Ionis, Karus Therapeutics, Nanostring, Pfizer, Takeda/Millennium Pharmaceuticals, and Tesaro; has ownership interest in Catena Pharmaceuticals, PTV Ventures, and Spindle Top Ventures; and is a consultant/advisory board member of AstraZeneca, Catena Pharmaceuticals, Critical Outcome Technologies, ImmunoMET, Ionis, Medimmune, Nuevolution, Pfizer, Precision Medicine, Signalchem Lifesciences, Symphogen, Takeda/Millennium Pharmaceuticals, and Tarveda. G.P. has received sponsored research support from Pifzer. No potential conflicts of interest were disclosed by the other authors.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Figures

Supplementary Figures 1–14

Reporting Summary

Supplementary Table 1

ARID1A mutation rate across cancer types

Supplementary Table 2

MS peptides in Vector- and ARID1A-expressing 293T cells

Supplementary Table 3

Ingenuity pathway analysis of ARID1A-interacting proteins

Supplementary Table 4

Mutation load in tumors with wild-type or mutant ARID1A, BRG1

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shen, J., Ju, Z., Zhao, W. et al. ARID1A deficiency promotes mutability and potentiates therapeutic antitumor immunity unleashed by immune checkpoint blockade. Nat Med 24, 556–562 (2018). https://doi.org/10.1038/s41591-018-0012-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41591-018-0012-z

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing