Genomic instability and the tumor microenvironment in breast cancer
Genomic instability and the tumor microenvironment in breast cancer
The efficacy of immunotherapy in breast cancer is largely dictated by the state of the tumor immune microenvironment (TIME). This thesis of Shibo Yu explores three key determinants: the cGAS-STING pathway activated by genomic instability, a histopathology feature, known as mature tertiary lymphoid structures (TLS), and the TME difference in metastatic breast cancer patients.
The findings reveal that the cGAS-STING pathway is highly active in triple-negative breast cancer, where its activation is positively associated with Cyclin E1-driven genomic instability. This pathway also correlates with increased immune infiltration and improved response to immune checkpoint inhibitors. Mechanistically, Cyclin E1 overexpression was demonstrated to induce micronuclei formation and activation of innate immune signaling. Furthermore, the presence of mature TLS was identified as an independent prognostic factor for improved survival and a robust predictor of favorable immunotherapy response. Ultimately, spatial transcriptomic analysis revealed differences in the TIME between paired primary tumor and distant metastases in breast cancer patients, while the epithelial tumor cell compartment remained consistent.
In conclusion, this work investigates the clinical relevance of the cGAS-STING pathway and its association with Cyclin E1, while also elucidating the clinical significance of mature TLS and TME difference in metastatic breast cancer patients. These findings provide a strong background to guide future breast cancer treatment strategies.