Session Item

Genomic instability and inflammation are intricately connected hallmark features of cancer. DNA damage in tumor cells can occur due to cancer-associated DNA repair defects, oncogene-induced replication stress or genotoxic cancer treatments. Unresolved DNA lesions can instigate signaling through the cGAS/STING pathway. The subsequent inflammatory signaling provides both tumor-suppressive as well as tumor-promoting traits.

To prevent clearance by the immune system, cancer cells need to adapt to escape immune surveillance. Currently, it is unclear how genomically unstable cancers, including triple-negative breast cancer (TNBCs), are rewired to escape immune clearance. I will discuss our studies on the mechanisms by which genomic instability triggers inflammatory signaling and describe adaptive mechanisms by which cancer cells can 'fly under the radar' of the immune system, and the therapeutic consequences thereof.

Specifically, I will discuss the strong correlation between MYC expression and loss of immune signatures in human TNBC. In mouse models of TNBC proficient or deficient of breast cancer type 1 susceptibility gene (BRCA1), MYC overexpression dramatically decreased lymphocyte infiltration in tumors, along with immune signature remodeling. MYC-mediated suppression of inflammatory signaling induced by BRCA1/2 inactivation was confirmed in human TNBC cell lines. Moreover, MYC overexpression prevented the recruitment and activation of lymphocytes in both human and mouse TNBC co-culture models. Chromatin-immunoprecipitation-sequencing revealed that MYC, together with its co-repressor MIZ1, directly binds promoters of multiple interferon-signaling genes, resulting in their downregulation. Together, our data revealed that MYC suppresses innate immunity and facilitates tumor immune escape, explaining the poor immunogenicity of MYC-overexpressing TNBCs.