Targeting cancer-associated fibroblast autophagy renders pancreatic cancer eradicable with immunochemotherapy by inhibiting adaptive immune resistance

Xiaozhen Zhang; Mengyi Lao; Hanshen Yang; Kang Sun; Yunfei Dong; Lihong He; Xinchi Jiang; Honghui Wu; Yangwei Jiang; Muchun Li; Honggang Ying; Xinyuan Liu; Jian Xu; Yan Chen; Hanjia Zhang; Ruhong Zhou; Jianqing Gao; Xueli Bai; Tingbo Liang

doi:10.1080/15548627.2023.2300913

Targeting cancer-associated fibroblast autophagy renders pancreatic cancer eradicable with immunochemotherapy by inhibiting adaptive immune resistance

Autophagy. 2024 Jan 4:1-21. doi: 10.1080/15548627.2023.2300913. Online ahead of print.

Authors

Xiaozhen Zhang^{1

2}, Mengyi Lao^{1

2}, Hanshen Yang^{1

2}, Kang Sun^{1

2}, Yunfei Dong³, Lihong He^{1

2}, Xinchi Jiang^{3

4}, Honghui Wu³, Yangwei Jiang⁵, Muchun Li^{1

2}, Honggang Ying^{1

2}, Xinyuan Liu^{1

2}, Jian Xu^{1

2}, Yan Chen^{1

2}, Hanjia Zhang^{1

2}, Ruhong Zhou^{5

6}, Jianqing Gao^{3

4

7

8}, Xueli Bai^{1

2

8}, Tingbo Liang^{1

2

8}

Affiliations

¹ Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
² Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
³ College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, PR China.
⁴ Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang University, Hangzhou, Zhejiang, PR China.
⁵ Institute of Quantitative Biology, College of Life Sciences, and Shanghai Institute for Advanced Study, Zhejiang University, Hangzhou, Zhejiang, China.
⁶ Department of Chemistry, Columbia University, New York, NY, USA.
⁷ Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China.
⁸ Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China.

PMID: 38174993
DOI: 10.1080/15548627.2023.2300913

Abstract

Accumulating evidence suggests that cancer-associated fibroblast (CAF) macroautophagy/autophagy is crucial in tumor development and may be a therapeutic target for pancreatic ductal adenocarcinoma (PDAC). However, the role of CAF autophagy during immune surveillance and cancer immunotherapy is unclear. The present study revealed that the inhibition of CAF autophagy suppresses in vivo tumor development in immune-deficient xenografts. This deletion compromises anti-tumor immunity and anti-tumor efficacy both in vitro and in vivo by upregulating CD274/PDL1 levels in an immune-competent mouse model. A block in CAF autophagy reduced the production of IL6 (interleukin 6), disrupting high desmoplastic TME and decreasing USP14 expression at the transcription level in pancreatic cancer cells. We further identify USP14 as the post-translational factor responsible for downregulating CD274 expression by removing K63 linked-ubiquitination at the K280 residue. Finally, chloroquine diphosphate-loaded mesenchymal stem cell (MSC)-liposomes, by accurately targeting CAFs, inhibited CAF autophagy, improving the efficacy of immunochemotherapy to combat pancreatic cancer.Abbreviation: AIR: adaptive immune resistance; ATRA: all-trans-retinoicacid; CAF: cancer-associated fibroblast; CD274/PDL1: CD274 molecule; CM: conditioned medium; CQ: chloroquine diphosphate; CyTOF: Mass cytometry; FGF2/bFGF: fibroblast growth factor 2; ICB: immune checkpoint blockade; IF: immunofluorescence; IHC: immunohistochemistry; IP: immunoprecipitation; MS: mass spectrometer; MSC: mesenchymal stem cell; PDAC: pancreatic ductal adenocarcinoma; TEM: transmission electron microscopy; TILs: tumor infiltrating lymphocytes; TME: tumor microenvironment; USP14: ubiquitin specific peptidase 14.

Keywords: Adaptive immune resistance; autophagy; cancer-associated fibroblast; pancreatic ductal adenocarcinoma; programmed cell death 1 ligand 1.