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Nature. 2017 Aug 24;548(7668):466-470. doi: 10.1038/nature23470. Epub 2017 Jul 31.

Mitotic progression following DNA damage enables pattern recognition within micronuclei.

Author information

1
Department of Cancer Biology, Basser Center for BRCA, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, 421 Curie Boulevard, Philadelphia, Pennsylvania 19104, USA.
2
Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
3
Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
4
Parker Institute for Cancer Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
5
Physical Sciences Oncology Center at Penn, 129 Towne Building, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
6
Molecular and Cell Biophysics Lab, 129 Towne Building, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
7
Graduate Group, Department of Physics and Astronomy, 129 Towne Building, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.

Abstract

Inflammatory gene expression following genotoxic cancer therapy is well documented, yet the events underlying its induction remain poorly understood. Inflammatory cytokines modify the tumour microenvironment by recruiting immune cells and are critical for both local and systemic (abscopal) tumour responses to radiotherapy. A poorly understood feature of these responses is the delayed onset (days), in contrast to the acute DNA-damage responses that occur in minutes to hours. Such dichotomous kinetics implicate additional rate-limiting steps that are essential for DNA-damage-induced inflammation. Here we show that cell cycle progression through mitosis following double-stranded DNA breaks leads to the formation of micronuclei, which precede activation of inflammatory signalling and are a repository for the pattern-recognition receptor cyclic GMP-AMP synthase (cGAS). Inhibiting progression through mitosis or loss of pattern recognition by stimulator of interferon genes (STING)-cGAS impaired interferon signalling. Moreover, STING loss prevented the regression of abscopal tumours in the context of ionizing radiation and immune checkpoint blockade in vivo. These findings implicate temporal modulation of the cell cycle as an important consideration in the context of therapeutic strategies that combine genotoxic agents with immune checkpoint blockade.

PMID:
28759889
PMCID:
PMC5857357
DOI:
10.1038/nature23470
[Indexed for MEDLINE]
Free PMC Article

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