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

• Published in: Science advances Vol. 5; no. 5; p. eaau5240
• Main Authors: Feng, M, Jin, J Q, Xia, L, Xiao, T, Mei, S, Wang, X, Huang, X, Chen, J, Liu, M, Chen, C, Rafi, S, Zhu, A X, Feng, Y-X, Zhu, D
• Format: Journal Article
• Language: English
• Published: United States 01-05-2019
• Subjects: Animals; Antineoplastic Agents, Immunological - metabolism; Antineoplastic Agents, Immunological - pharmacology; beta Catenin - antagonists & inhibitors; beta Catenin - metabolism; 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
• ISSN: 2375-2548; 2375-2548
• DOI: 10.1126/sciadv.aau5240

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