Pharmacological inhibition of β-catenin/BCL9 interaction overcomes resistance to immune checkpoint blockades by modulating Treg cells
Pharmacological inhibition of β-catenin/BCL9 interaction overcomes resistance to immune checkpoint blockades by modulating Treg cells
复制标题
β-catenin/BCL9 相互作用的药理学抑制通过调节 Treg 细胞克服对免疫检查点阻断的抵抗
DOI：
10.1126/sciadv.aau5240
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发表时间：
2019-05-01
期刊：
影响因子：
13.6
通讯作者：
Zhu, D.
中科院分区：
文献类型：
--
作者：
Feng, M.;Jin, J. Q.;Zhu, D.
Wnt/β-连环蛋白（β-cat）通路在癌症中起着关键作用。使用碳氢化合物钉合肽技术，我们的目标是通过破坏β-cat与其共激活因子B细胞淋巴瘤9（BCL 9）和B细胞淋巴瘤9样（B 9 L）的相互作用来开发针对该途径的有效的选择性抑制剂。我们鉴定了一组肽，包括hsBCL 9（CT）-24，其强烈抑制β-cat的活性并抑制癌细胞生长。在动物模型中，这些肽表现出有效的抗肿瘤作用、有利的药代动力学特征和最小的毒性。显著地，这些肽通过减少调节性T细胞（T-reg）和增加树突状细胞（DC）促进细胞毒性T细胞的肿瘤内浸润，因此使癌细胞对PD-1抑制剂敏感。鉴于结直肠癌中T-reg浸润和APC突变之间的强相关性，这表明我们的肽可以重新激活由致癌Wnt途径抑制的抗癌免疫应答。总之，我们报告了一种通过药理学抑制Wnt/β-cat信号传导的有前景的癌症治疗策略。
The Wnt/beta-catenin (beta-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 beta-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 beta-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/beta-cat signaling.