Targeting MFAP5 in cancer-associated fibroblasts sensitizes pancreatic cancer to PD-L1-based immunochemotherapy via remodeling the matrix

Author(s): Yi Duan ¹ ^, ² ^, ³ ^, ⁴ ^, ⁵ ^, ⁶ , Xiaozhen Zhang ¹ ^, ² ^, ³ ^, ⁴ ^, ⁵ ^, ⁶ , Honggang Ying ¹ ^, ² ^, ³ ^, ⁴ ^, ⁵ ^, ⁶ , Jian Xu ¹ ^, ² ^, ³ ^, ⁴ ^, ⁵ ^, ⁶ , Hanshen Yang ¹ ^, ² ^, ³ ^, ⁴ ^, ⁵ ^, ⁶ , Kang Sun ¹ ^, ² ^, ³ ^, ⁴ ^, ⁵ ^, ⁶ , Lihong He ¹ ^, ² ^, ³ ^, ⁴ ^, ⁵ ^, ⁶ , Muchun Li ¹ ^, ² ^, ³ ^, ⁴ ^, ⁵ ^, ⁶ , Yongtao Ji ¹ ^, ² ^, ³ ^, ⁴ ^, ⁵ ^, ⁶ , Tingbo Liang ¹ ^, ² ^, ³ ^, ⁴ ^, ⁵ ^, ⁶ ^, , Xueli Bai ¹ ^, ² ^, ³ ^, ⁴ ^, ⁵ ^, ⁶ ^,

Publication date (Electronic): 8 May 2023

Journal: Oncogene

Publisher: Nature Publishing Group UK

Keywords: Cancer microenvironment, Tumour immunology, Acetylation

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Abstract

Highly desmoplastic and immunosuppressive tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC) contributes to tumor progression and resistance to current therapies. Clues targeting the notorious stromal environment have offered hope for improving therapeutic response whereas the underlying mechanism remains unclear. Here, we find that prognostic microfibril associated protein 5 (MFAP5) is involved in activation of cancer-associated fibroblasts (CAFs). Inhibition of MFAP5 ^highCAFs shows synergistic effect with gemcitabine-based chemotherapy and PD-L1-based immunotherapy. Mechanistically, MFAP5 deficiency in CAFs downregulates HAS2 and CXCL10 via MFAP5/RCN2/ERK/STAT1 axis, leading to angiogenesis, hyaluronic acid (HA) and collagens deposition reduction, cytotoxic T cells infiltration, and tumor cells apoptosis. Additionally, in vivo blockade of CXCL10 with AMG487 could partially reverse the pro-tumor effect from MFAP5 overexpression in CAFs and synergize with anti-PD-L1 antibody to enhance the immunotherapeutic effect. Therefore, targeting MFAP5 ^highCAFs might be a potential adjuvant therapy to enhance the immunochemotherapy effect in PDAC via remodeling the desmoplastic and immunosuppressive microenvironment.

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Most cited references 49

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Daniel Chen, Ira Mellman (2017)

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Author and article information

Contributors

Tingbo Liang: liangtingbo@zju.edu.cn

Xueli Bai:

ORCID: http://orcid.org/0000-0002-2934-0880

shirleybai@zju.edu.cn

Journal

Journal ID (nlm-ta): Oncogene

Journal ID (iso-abbrev): Oncogene

Title: Oncogene

Publisher: Nature Publishing Group UK (London )

ISSN (Print): 0950-9232

ISSN (Electronic): 1476-5594

Publication date (Electronic): 8 May 2023

Publication date PMC-release: 8 May 2023

Publication date (Print): 2023

Volume: 42

Issue: 25

Pages: 2061-2073

Affiliations

[1 ]GRID grid.13402.34, ISNI 0000 0004 1759 700X, Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, School of Medicine, , Zhejiang University, ; Hangzhou, 310000 Zhejiang China

[2 ]GRID grid.13402.34, ISNI 0000 0004 1759 700X, Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, School of Medicine, , Zhejiang University, ; Hangzhou, 310000 Zhejiang China

[3 ]GRID grid.13402.34, ISNI 0000 0004 1759 700X, Zhejiang Provincial Innovation Center for The Study of Pancreatic Diseases, , Zhejiang University, ; Hangzhou, 310000 Zhejiang China

[4 ]GRID grid.13402.34, ISNI 0000 0004 1759 700X, Zhejiang Provincial Clinical Research Center for The Study of Hepatobiliary & Pancreatic Diseases, , Zhejiang University, ; Hangzhou, 310000 China

[5 ]GRID grid.13402.34, ISNI 0000 0004 1759 700X, Cancer Center, , Zhejiang University, ; Hangzhou, 310000 China

[6 ]GRID grid.510538.a, ISNI 0000 0004 8156 0818, Research Center for Healthcare Data Science, Zhejiang Lab, ; Hangzhou, 310000 Zhejiang China

Author information

Xueli Bai http://orcid.org/0000-0002-2934-0880

Article

Publisher ID: 2711

DOI: 10.1038/s41388-023-02711-9

PMC ID: 10275759

PubMed ID: 37156839

SO-VID: e5eee82b-8166-4420-bbbd-0d157dec3bc7

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 25 November 2022

Date revision received : 20 April 2023

Date accepted : 24 April 2023

Funding

Funded by: National Natural Science Foundation of China:81871925 and 82071867, the Key Research and Development Program of Zhejiang Province:2020C03117, the Fundamental Research Funds for the Zhejiang Provincial Universities: 2021XZZX031

Funded by: National Key Research and Development Program grant:2019YFC1316000, National Natural Science Foundation of China:U20A20378 and 81830089, the Key Research and Development Program of Zhejiang Province:019C03019, the Major Scientific Project of Zhejiang Lab:2020ND8AD01

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: cancer microenvironment,tumour immunology,acetylation

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: cancer microenvironment, tumour immunology, acetylation

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Targeting MFAP5 in cancer-associated fibroblasts sensitizes pancreatic cancer to PD-L1-based immunochemotherapy via remodeling the matrix

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Most cited references 49

Cancer Statistics, 2021

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Elements of cancer immunity and the cancer–immune set point

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