Pharmacological inhibition of β-catenin/BCL9 interaction overcomes resistance to immune checkpoint blockades by modulating Treg cells

  • Sci Adv. 2019 May 8;5(5):eaau5240. doi: 10.1126/sciadv.aau5240.
M Feng  1 ,  J Q Jin  2 ,  L Xia  1 ,  T Xiao  3 ,  S Mei  4 ,  X Wang  1 ,  X Huang  1 ,  J Chen  1 ,  M Liu  2 ,  C Chen  3 ,  S Rafi  5 ,  A X Zhu  6 ,  Y-X Feng  7  8 ,  D Zhu  1
Affiliations
  • 1. School of Pharmacy, Fudan University, Shanghai, 201203, China.
  • 2. Harvard College, Harvard University, Cambridge, MA 02138, USA.
  • 3. Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02145, USA.
  • 4. Department of Bioinformatics, School of Life Sciences and Technology, Tongji University, Shanghai, China.
  • 5. Schrödinger, LLC, Cambridge, MA 02142, USA.
  • 6. Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA.
  • 7. The First Affiliated Hospital, Zhejiang University School of Medicine, Institute of Translational Medicine, Zhejiang University, Hangzhou 310029, China.
  • 8. Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
PMID: 31086813 DOI: 10.1126/sciadv.aau5240
Abstract

The Wnt/β-catenin (β-cat) pathway plays a critical role in Cancer. Using hydrocarbon-stapled peptide technologies, we aim to develop potent, selective inhibitors targeting this pathway by disrupting the interaction of β-cat with its coactivators B-cell lymphoma 9 (BCL9) and B-cell lymphoma 9-like (B9L). We identified a set of peptides, including hsBCL9CT-24, that robustly inhibits the activity of β-cat and suppresses Cancer cell growth. In animal models, these peptides exhibit potent anti-tumor effects, favorable pharmacokinetic profiles, and minimal toxicities. Markedly, these peptides promote intratumoral infiltration of cytotoxic T cells by reducing regulatory T cells (Treg) and increasing dendritic cells (DCs), therefore sensitizing Cancer cells to PD-1 inhibitors. Given the strong correlation between Treg infiltration and APC mutation in colorectal cancers, it indicates our peptides can reactivate anti-cancer immune response suppressed by the oncogenic Wnt pathway. In summary, we report a promising strategy for Cancer therapy by pharmacological inhibition of the Wnt/β-cat signaling.

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