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Theranostics 2023; 13(10):3371-3386. doi:10.7150/thno.83377 This issue Cite

Research Paper

Targeting β-catenin and PD-L1 simultaneously by a racemic supramolecular peptide for the potent immunotherapy of hepatocellular carcinoma

Zhengjun Zhou1,2,†, Xiao Li1,†, Guang Yang3,†,✉, Jingmei Wang4, Baohua Li5, Yinong Huang6,✉, Jin Yan2,✉, Kaishan Tao1,✉

1. Department of Hepatobiliary and Pancreaticosplenic Surgery, Xijing Hospital, Air Force Medical University (The Fourth Military Medical University), Xi'an 710032, China.
2. National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, China.
3. Department of Oncology, Suzhou BenQ Medical Center, The Affiliated BenQ Hospital of Nanjing Medical University, Suzhou, Jiangsu Province, China.
4. Institute for Stem Cell & Regenerative Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China.
5. Core Research Laboratory, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China.
6. Shaanxi Institute of Pediatric Diseases, Xi'an Children's Hospital, Xi'an, 710003, China.
† These authors contributed equally.

✉ Corresponding authors: Email: yangguang9002com (G. Yang); Email: ynhuangedu.cn (Y. Huang); Email: yanjin19920602edu.cn (J. Yan); Email: taokaishan0686com (K. Tao).

Citation:
Zhou Z, Li X, Yang G, Wang J, Li B, Huang Y, Yan J, Tao K. Targeting β-catenin and PD-L1 simultaneously by a racemic supramolecular peptide for the potent immunotherapy of hepatocellular carcinoma. Theranostics 2023; 13(10):3371-3386. doi:10.7150/thno.83377. https://www.thno.org/v13p3371.htm
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Abstract

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Objective: The low clinical utility of immune checkpoint inhibitors (ICIs) against PD-1 or PD-L1 has recently been associated with the activation of the Wnt/β-catenin signaling pathway in hepatocellular carcinoma (HCC), which promotes tumor immune escape and resistance to anti-PD-1/PD-L1 therapy. Hence, we aimed to fabricate a supramolecular peptide which could target the Wnt/β-catenin signaling pathway coupled with ICIs blockage therapy for optimizing HCC immunotherapy.

Methods: A racemic spherical supramolecular peptide termed sBBI&PDP nanoparticle was constructed by hierarchical self-assembly, comprising an L-enantiomeric peptide as an inhibitor of BCL9 and β-catenin (sBBI) and a D-enantiomeric peptide as an inhibitor of PD-1/PD-L1 (PDP).

Results: sBBI&PDP nanoparticle potently suppressed the hyperactivated Wnt/β-catenin signaling pathway in vitro and in vivo, while blocking endogenous PD-L1 effectively. Furthermore, sBBI&PDP increased the infiltration and action of CD8+ T cells at tumor sites. Notably, compared with the original sBBI and commercial Anti-PD-L1 inhibitors, the designed sBBI&PDP showed stronger antitumor efficacy in an orthotopic homograft mice model of HCC and a PDX HCC model in Hu-PBMC-NSG mice. Moreover, sBBI&PDP possessed a favorable biosafety profile.

Conclusion: The successful implementation of this strategy could revitalize ICIs blockage therapy and promote the discovery of artificial peptides for HCC immunotherapy.

Keywords: supramolecular peptide, β-catenin, PD-L1, tumor immunotherapy, hepatocellular carcinoma

Citation styles

APA
Zhou, Z., Li, X., Yang, G., Wang, J., Li, B., Huang, Y., Yan, J., Tao, K. (2023). Targeting β-catenin and PD-L1 simultaneously by a racemic supramolecular peptide for the potent immunotherapy of hepatocellular carcinoma. Theranostics, 13(10), 3371-3386. https://doi.org/10.7150/thno.83377.

ACS
Zhou, Z.; Li, X.; Yang, G.; Wang, J.; Li, B.; Huang, Y.; Yan, J.; Tao, K. Targeting β-catenin and PD-L1 simultaneously by a racemic supramolecular peptide for the potent immunotherapy of hepatocellular carcinoma. Theranostics 2023, 13 (10), 3371-3386. DOI: 10.7150/thno.83377.

NLM
Zhou Z, Li X, Yang G, Wang J, Li B, Huang Y, Yan J, Tao K. Targeting β-catenin and PD-L1 simultaneously by a racemic supramolecular peptide for the potent immunotherapy of hepatocellular carcinoma. Theranostics 2023; 13(10):3371-3386. doi:10.7150/thno.83377. https://www.thno.org/v13p3371.htm

CSE
Zhou Z, Li X, Yang G, Wang J, Li B, Huang Y, Yan J, Tao K. 2023. Targeting β-catenin and PD-L1 simultaneously by a racemic supramolecular peptide for the potent immunotherapy of hepatocellular carcinoma. Theranostics. 13(10):3371-3386.

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