Microbiota-Derived Bile Acids Enhances T Cell-Mediated Anti-Tumor Immunity via the Androgen Receptor

Principal Investigator:

Chun-Jun Guo, Associate Professor of Immunology in Medicine

Background & Unmet Need

Androgen receptor (AR) signaling plays a crucial role in tumor development, progression, and treatment response, particularly affecting immune checkpoint blockade efficacy
Similarly, the gut microbiome significantly influences cancer outcomes and immunotherapy success, but the underlying molecular mechanisms remain poorly understood
The gut microbiome produces numerous bile acids with diverse biological functions, with recent studies revealing their important immunomodulatory functions
The relationship between microbiota-derived bile-acids and AR signaling remains unexplored
Unmet Need: Novel AR antagonists are needed to overcome treatment resistance and improve cancer therapy outcomes

Technology Overview

The Technology: Novel E. coli strains engineered to produce AR-antagonizing bile acids for treating androgen-dependent cancers
The Discovery: Four previously uncharacterized microbiota-derived bile acids (including 3-oxo-Δ5-LCA, 3-oxo-Δ4-LCA, 3-oxo-Δ4,6-LCA and 3-oxo-LCA) act as potent AR antagonists
PoC Data: The identified BA compounds specifically bind to AR ligand binding domain and suppress AR-dependent gene expression (Kd = 0.8-2.4 µM)
Treatment with 3-oxo-Δ4,6-LCA reduced tumor volume by >80% and significantly decreased lung metastasis burden compared to no treatment
3-oxo-Δ4,6-LCA treatment increased tumor-infiltrating stem-like CD8+ T cells by 2.5-fold
When combined with anti-PD-1 therapy, 3-oxo-Δ4,6-LCA enhanced therapeutic efficacy, leading to 90% reduction in tumor growth compared to anti-PD-1 alone

Technology Applications

Treatment of AR-dependent cancers (bladder, urothelial, prostate, kidney, or lung)
As an adjuvants to enhance immunotherapy efficacy
Manufacturing tool to produce bile acids with engineered E. Coli strains

Technology Advantages