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.

  • Research Highlight
  • Published:

Immunotherapy

dMMR presents opportunities to enhance immunotherapy

Nature Reviews Clinical Oncology volume 15, page 67 (2018)Cite this article

Subjects

Tumours with DNA mismatch repair deficiency (dMMR) often develop and progress rapidly, but are paradoxically associated with a favourable prognosis. Such tumours are also particularly responsive to immune-checkpoint blockade, as underscored by the recent histology-agnostic approval of pembrolizumab for the treatment of dMMR tumours. The functional basis of these clinical observations remains unclear, but has been hypothesized to reflect an increased mutation rate that results in the generation of neoantigens by, and thus improved immunosurveillance of, dMMR cancer cells. New data from a preclinical study support the validity of this theory.

In this study, Alberto Bardelli and colleagues induced dMMR in mouse colorectal, breast, and pancreatic cancer cell lines by inactivating Mlh1, the MMR gene that is most frequently altered in colorectal cancers. Despite having similar growth kinetics to their MMR-proficient counterparts in vitro and in immunocompromised mice, the dMMR cells grew poorly when implanted in immunoproficient syngeneic mice. “We found that inactivation of dMMR increased mutability and concomitantly augmented the neoantigen burden that dynamically evolved over time,” Bardelli explains. By contrast, the mutational load and neoantigen profile of the MMR-proficient cells remained stable. Accordingly, tumours comprising dMMR cells, but not their parental counterparts, effectively triggered immunosurveillance and regressed in response to immune-checkpoint inhibition in mice. “Overall, our results suggest that dMMR causes a dynamic hypermutation status that leads to continuous generation of neoantigens in tumours, which improves immune surveillance,” Bardelli summarizes.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

References

  1. Germano, G. et al. Inactivation of DNA repair triggers neoantigen generation and impairs tumour growth. Nature 552, 116–120 (2017)

    Article  CAS  PubMed  Google Scholar 

Download references

Authors
  1. David Killock
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Killock, D. dMMR presents opportunities to enhance immunotherapy. Nat Rev Clin Oncol 15, 67 (2018). https://doi.org/10.1038/nrclinonc.2017.203

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrclinonc.2017.203

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer