Pancreatic tumor eradication via selective Pin1 inhibition in cancer-associated fibroblasts and T lymphocytes engagement

Jiaye Liu, Yang Wang, Chunyang Mu, Meng Li, Kewei Li, Shan Li, Wenshuang Wu, Lingyao Du, Xiaoyun Zhang, Chuan Li, Wei Peng, Junyi Shen, Yang Liu, Dujiang Yang, Kaixiang Zhang, Qingyang Ning, Xiaoying Fu, Yu Zeng, Yinyun Ni, Zongguang Zhou, Yi Liu, Yiguo Hu, Xiaofeng Zheng (), Tianfu Wen (), Zhihui Li () and Yong Liu ()
Additional contact information
Jiaye Liu: Sichuan University
Yang Wang: Karolinska Institute
Chunyang Mu: Sichuan University
Meng Li: Chinese Academy of Sciences
Kewei Li: Sichuan University
Shan Li: Army Medical University
Wenshuang Wu: Sichuan University
Lingyao Du: Sichuan University
Xiaoyun Zhang: Sichuan University
Chuan Li: Sichuan University
Wei Peng: Sichuan University
Junyi Shen: Sichuan University
Yang Liu: Sichuan University
Dujiang Yang: Sichuan University
Kaixiang Zhang: Sichuan University
Qingyang Ning: Sichuan University
Xiaoying Fu: Sichuan University
Yu Zeng: Sichuan University
Yinyun Ni: Sichuan University
Zongguang Zhou: Sichuan University
Yi Liu: Sichuan University
Yiguo Hu: Sichuan University and Collaborative Innovation Center
Xiaofeng Zheng: Sichuan University
Tianfu Wen: Sichuan University
Zhihui Li: Sichuan University
Yong Liu: Sichuan University

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract Cancer associated fibroblasts (CAFs) support tumors via multiple mechanisms, including maintaining the immunosuppressive tumor microenvironment and limiting infiltration of immune cells. The prolyl isomerase Pin1, whose overexpression in CAFs has not been fully profiled yet, plays critical roles in tumor initiation and progression. To decipher effects of selective Pin1 inhibition in CAFs on pancreatic cancer, here we formulate a DNA-barcoded micellular system (DMS) encapsulating the Pin1 inhibitor AG17724. DMS functionalized with CAF-targeting anti-FAP-α antibodies (antiCAFs-DMS) can selectively inhibit Pin1 in CAFs, leading to efficacious but transient tumor growth inhibition. We further integrate DNA aptamers (AptT), which can engage CD8+ T lymphocytes, to obtain a bispecific antiCAFs-DMS-AptT system. AntiCAFs-DMS-AptT inhibits tumor growth in subcutaneous and orthotopic pancreatic cancer models.

Date: 2022
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31928-7

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DOI: 10.1038/s41467-022-31928-7

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