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

M Feng; J Q Jin; L Xia; T Xiao; S Mei; X Wang; X Huang; J Chen; M Liu; C Chen; S Rafi; A X Zhu; Y-X Feng; D Zhu

doi:10.1126/sciadv.aau5240

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

Sci Adv. 2019 May 8;5(5):eaau5240. doi: 10.1126/sciadv.aau5240. eCollection 2019 May.

Authors

M Feng¹, J Q Jin², L Xia¹, T Xiao³, S Mei⁴, X Wang¹, X Huang¹, J Chen¹, M Liu², C Chen³, S Rafi⁵, A X Zhu⁶, Y-X Feng^{7

8}, D Zhu¹

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.

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 hsBCL9_CT-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 (T_reg) and increasing dendritic cells (DCs), therefore sensitizing cancer cells to PD-1 inhibitors. Given the strong correlation between T_reg 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents, Immunological / metabolism
Antineoplastic Agents, Immunological / pharmacology
Cell Line, Tumor
Cell Proliferation / drug effects
Chemokine CCL20 / antagonists & inhibitors
Chemokine CCL20 / metabolism
Chemokine CCL22 / antagonists & inhibitors
Chemokine CCL22 / metabolism
Colorectal Neoplasms / metabolism
Colorectal Neoplasms / pathology
Female
Humans
Mice
Mice, Inbred BALB C
Mice, Nude
Peptides / metabolism
Peptides / pharmacology
T-Lymphocytes, Cytotoxic / cytology
T-Lymphocytes, Cytotoxic / immunology
T-Lymphocytes, Cytotoxic / metabolism
T-Lymphocytes, Regulatory / cytology
T-Lymphocytes, Regulatory / immunology*
T-Lymphocytes, Regulatory / metabolism
Transcription Factors / antagonists & inhibitors
Transcription Factors / chemistry
Transcription Factors / metabolism*
Transplantation, Heterologous
Wnt Signaling Pathway / drug effects
beta Catenin / antagonists & inhibitors
beta Catenin / metabolism*

Substances

Antineoplastic Agents, Immunological
BCL9 protein, human
Chemokine CCL20
Chemokine CCL22
Peptides
Transcription Factors
beta Catenin

Associated data

figshare/10.6084/m9.figshare.5624863.v1