LXR-inverse agonism stimulates immune-mediated tumor destruction by enhancing CD8 T-cell activity in triple negative breast cancer
Abstract
Triple-negative breast cancer (TNBC) is a highly aggressive subtype that is untreatable with hormonal or HER2-targeted therapies and is also typically unresponsive to checkpoint-blockade immunotherapy. Within the tumor microenvironment dysregulated immune cell metabolism has emerged as a key mechanism of tumor immune-evasion. We have discovered that the Liver-X-Receptors (LXRα and LXRβ), nuclear receptors known to regulate lipid metabolism and tumor-immune interaction, are highly activated in TNBC tumor associated myeloid cells. We therefore theorized that inhibiting LXR would induce immune-mediated TNBC-tumor clearance. Here we show that pharmacological inhibition of LXR activity induces tumor destruction primarily through stimulation of CD8+ T-cell cytotoxic activity and mitochondrial metabolism. Our results imply that LXR inverse agonists may be a promising new class of TNBC immunotherapies.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Dec 20, 2019
- Source ID
- 10.1038/s41598-019-56038-1
Entities
People
- Arindam Chatterjee
- Aurore-cecile Valfort
- Colin A Flaveny
- Jinsong Zhang
- Katherine J. Carpenter
- Laurie P. Shornick
- Monideepa Sengupta
- Nick Steinauer
- Richard J. Di Paolo
- Shabnam Majidi
- Suomia Abuirqeba
Organizations
- Office of Extramural Research
- United States Department of Defense