Cell cycle checkpoints cooperate to suppress DNA and RNA associated molecular pattern recognition and anti-tumor immune responses
Shane M. Harding,
Joseph L. Benci,
Andy J. Minn,
Irfan A Asangani,
Roger A Greenberg
Posted 24 Jun 2020
bioRxiv DOI: 10.1101/2020.06.24.168971 (published DOI: 10.1016/j.celrep.2020.108080)
Posted 24 Jun 2020
The DNA dependent pattern recognition receptor, cGAS mediates communication between genotoxic stress and the immune system. Mitotic chromosome missegregation is an established stimulator of cGAS activity, however, it is unclear if progression through mitosis is required for cancer cell intrinsic activation of immune mediated anti-tumor responses. Moreover, it is unknown if disruption of cell cycle checkpoints can restore responses in cancer cells that are recalcitrant to DNA damage induced inflammation. Here we demonstrate that prolonged cell cycle arrest at the G2-mitosis boundary from either CDK1 inhibition or excessive DNA damage prevents inflammatory stimulated gene expression and immune mediated destruction of distal tumors. Remarkably, DNA damage induced inflammatory signaling is restored in a cGAS- and RIG-I- dependent manner upon concomitant disruption of p53 and the G2 checkpoint. These findings link aberrant cell progression and p53 loss to an expanded spectrum of damage associated molecular pattern recognition and have implications for the design of rational approaches to augment anti-tumor immune responses. ### Competing Interest Statement The authors have declared no competing interest.
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