Cell Cycle Checkpoints Cooperate to Suppress DNA- and RNA-Associated Molecular Pattern Recognition and Anti-Tumor Immune Responses

The DNA-dependent pattern recognition receptor, cGAS (cyclic GMP-AMP synthase), mediates communication between the DNA damage and the immune responses. Mitotic chromosome missegregation stimulates cGAS activity; however, it is unclear whether progression through mitosis is required for cancercell-intrinsic activation of anti-tumor immune responses. Moreover, it is unknown whether cell cycle checkpoint disruption can restore responses in cancer cells that are recalcitrant to DNAdamage-induced inflammation. Here, we demonstrate that prolonged cell cycle arrest at the G2-mitosis boundary from either excessive DNA damage or CDK1 inhibition prevents inflammatory-stimulated gene expression and immune-mediated destruction of distal tumors. Remarkably, DNAdamage-induced inflammatory signaling is restored in a 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. [Display omitted] •Prolonged arrest before mitosis prevents inflammation and anti-tumor immunity•Disruption of cell-cycle checkpoints restores inflammation in NHEJ-deficient cells•Combined loss of p53 and ATR activates cGAS- and RIG-I-dependent pattern recognition Chen et al. show that prolonged cell cycle arrest before mitosis prevents inflammatory signaling and anti-tumor immunity. Concomitant disruption of p53 and the G2 checkpoint restores DNA-damage-induced inflammatory signaling in a cGAS- and RIG-I-dependent manner.