DNA Repair Deficiency in Breast Cancer: Opportunities for Immunotherapy

Figure 1

STING pathway activation in DNA repair deficient breast cancer. Stalled replication forks or damaged DNA as a result of mutations in Fanconi Anemia/BRCA repair pathway genes results in cytosolic DNA, detected by cGAS. 2’3’-cGAMP is produced, which then activates STING. STING dimerises or oligomerises, and TBK1 and IRF3 are phosphorylated. IRF3 then translocates to the nucleus resulting in the expression of immune genes including CXCL10 and CCL5. Note: other downstream activators of the STING pathway, notably TRAF6 and NFκB, are not shown in this instance. CXCL10 and CCL5 are implicated in chemoattraction of CD8+ and CD4+ T-cells. However the tumor microenvironment may also contain immunosuppressive FoxP3+ CD4+ cells which express CTLA4, PD-1, PD-L1, LAG3, and TIM3; tumor-associated macrophages (TAMs) which express PD-1, PD-L1, CD80 and CD86, LAG3, and TIM3. Tumor infiltrating lymphocytes (TILs) may express CTLA4, PD-1, TIM3, and LAG3. Therefore, DNA repair deficiency results in activation of the cGAS-STING pathway which has both antitumorigenic and protumorigenic effects within the tumor microenvironment.