DNA Damage Response Deficiency (DDRD) in Breast Cancer is associated with a STING-dependent Innate Immune Response

Key Findings:

• DNA damage response deficient human breast cancers are associated with CD8+ and CD4+ lymphocytic infiltration.
• The epithelial component of DDRD tumors releases chemokines that can account for lymphocytic infiltration.
• Chemokine release is dependent on activation of the cGAS-STING-IRF3 pathway which is constitutively activated in DNA repair deficient cells, or by exogenous DNA damaging agents.
• Activation of the cGAS-STING-IRF3 pathway is cell cycle specific and is associated with an accumulation of cytosolic DNA in the S-phase of the cell cycle.
• Activation of the cGAS-STING-IRF3 pathway is associated with expression of the immune-checkpointinggene PD-L1 which may prevent immune-mediated tumorcell death.
• This may provide a therapeutic rationale for immune-checkpoint targeted therapies in the context of DNA damage response deficiency in cancer.