Targeting an Innate Immune Signaling Pathway to Treat TNBC
Abstract
Triple negative breast cancer (TNBC) remains a challenge to clinicians, laboratory investigators, and patients due to its disproportionate number of breast cancer deaths and its lack of an established therapeutic target. Numerous studies have identified potential novel mutational gene targets in TNBC, but single-agent therapeutics have lacked substantial impact in TNBC. More recently, immune checkpoint inhibitors gained significant clinical traction in breast cancer. Unfortunately, initial promising results have been subsequently overshadowed with failures, particularly in TNBC. In other solid human tumors, the efficacy of anti-PD-L1 immune checkpoint therapies appeared to be enhanced by stimulating lymphocyte infiltration into the tumor microenvironment with type I IFNs. We have now identified a similar IFN-stimulated pathway in TNBC. We show that TNBC cells express high levels of the RIG-I double-stranded RNA sensor and downstream active JAK1/STAT1/INF-b pathway components. Moreover, we show that TNBC cells display an interferon gene signature, suggesting that TNBC cells are primed to respond to type I IFNs. Further stimulation of this pathway would result in enhanced expression of PD-L1, a known transcriptional target of IFN-b, as well as the recruitment of IFN-responsive tumor infiltrating lymphocytes. We now propose to build on these exciting preliminary findings generated from our previous award with a series experiments aimed at determining the clinical utility of hyperactivating RIG-I and increasing IFN-b production to sensitize TNBC cells to immune checkpoint therapies.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2022
- Accession Number
- AD1190959
Entities
People
- Jason D Weber
Organizations
- Washington University in St. Louis