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 Jun;20(6):1314-1334. doi: 10.1080/15548627.2023.2300913. Epub 2024 Jan 11.

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.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptive Immunity / drug effects
Animals
Autophagy* / drug effects
B7-H1 Antigen / metabolism
Cancer-Associated Fibroblasts* / drug effects
Cancer-Associated Fibroblasts* / metabolism
Carcinoma, Pancreatic Ductal / drug therapy
Carcinoma, Pancreatic Ductal / immunology
Carcinoma, Pancreatic Ductal / pathology
Cell Line, Tumor
Chloroquine / pharmacology
Chloroquine / therapeutic use
Humans
Immunotherapy* / methods
Mice
Pancreatic Neoplasms* / drug therapy
Pancreatic Neoplasms* / immunology
Pancreatic Neoplasms* / pathology
Tumor Microenvironment* / drug effects

Substances

B7-H1 Antigen
Chloroquine

Grants and funding

This work was supported by grants from the National Key Research and Development Program [2019YFC1316000 to TBL]; the National Natural Science Foundation of China [U20A20378, 82188102 and 81830089 to TBL, 81871925 and 82071867 to XLB]; the Key Research and Development Program of Zhejiang Province [2019C03019 to TBL, 2020C03117 to XLB]; the Fundamental Research Funds for the Zhejiang Provincial Universities [2021XZZX031 to XLB]; and the Natural Science Foundation of Zhejiang Province (LD22H300002 to JQG)