Abstract C105: DNA damage response deficiency (DDRD) in breast cancer is associated with a STING-dependent innate immune response

Background In breast cancer the presence of an immune infiltration has been recognised as a prognostic factor, however the mechanisms underpinning this response are not clearly defined. Previously we identified a gene expression signature that defines a DNA damage response defective (DDRD) molecular subgroup in breast cancer, that is enriched for BRCA1 and 2 mutations, and has a good outcome following DNA-damaging chemotherapy. Importantly, this DDRD subgroup is associated with up-regulation of type I Interferon-related genes. We therefore investigated the mechanism activating this immune response in the context of abnormal DNA repair. Results IHC analysis demonstrated that both intra-tumoral and stromal CD8+ and CD4+ T cell infiltration were associated with DDRD positive breast tumors. The CXCL10 and CCL5 cytokines were shown to be significantly up-regulated in DDRD positive breast tumours and in tissue culture models for the DDRD molecular subgroup. Furthermore, conditioned media from DDRD positive cell lines stimulated inward migration of peripheral blood mononuclear cells, when compared to media from DDRD negative cells, indicating the presence of active cytokines. We identified constitutive activation of the innate immune pathway STING/TBK1/IRF3 specifically in DDRD positive cells when compared to DDRD negative cells and found that binding of the DNA sensor cGAS to cytosolic Histone H3 was required for this immune response. Treatment of HeLa cells with DNA damaging chemotherapies but not taxanes resulted in STING-dependent expression of CXCL10 and CCL5 cytokines. Conclusion We have identified that the STING/TBK1/IRF3 immune pathway is activated by endogenous DNA damage in DDRD breast cancers and may explain lymphocytic infiltration observed in this subtype of breast tumours. These data suggest that the DDRD signature can identify an innate immune response to DNA damage in breast cancer, which may have therapeutic applications for immune targeted therapies. Citation Format: Eileen E. Parkes, Steven M. Walker, Nuala McCabe, Laura E. Taggart, Laura Hill, Karen D. McCloskey, Niamh E. Buckley, Manuel Salto-Tellez, Paul B. Mullan, D. P. Harkin, Richard D. Kennedy. DNA damage response deficiency (DDRD) in breast cancer is associated with a STING-dependent innate immune response. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C105.