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  • CD64+ fibroblast-targeted vilanterol and a STING agonist augment CLDN18.2 BiTEs efficacy against pancreatic cancer by reducing desmoplasia and enriching stem-like CD8+ T cells

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Pancreas
Original research
CD64+ fibroblast-targeted vilanterol and a STING agonist augment CLDN18.2 BiTEs efficacy against pancreatic cancer by reducing desmoplasia and enriching stem-like CD8+ T cells
  1. Tianxing Zhou1,
  2. Xupeng Hou1,
  3. Jingrui Yan1,
  4. Lin Li1,
  5. Yongjie Xie1,
  6. Weiwei Bai1,
  7. Wenna Jiang2,
  8. Yiping Zou1,
  9. Xueyang Li1,
  10. Ziyun Liu1,
  11. Zhaoyu Zhang1,
  12. Bohang Xu1,
  13. Guohua Mao1,
  14. Yifei Wang1,
  15. Song Gao1,
  16. Xiuchao Wang1,
  17. Tiansuo Zhao1,
  18. Hongwei Wang1,
  19. Hongxia Sun1,3,
  20. Xiufeng Zhang4,
  21. Jun Yu1,
  22. Chongbiao Huang1,5,
  23. Jing Liu6,7,
  24. Jihui Hao1
  1. 1Pancreas Center, Department of pancreatic cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, National Key laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin Key laboratory of Digestive Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, People's Republic of China
  2. 2Department of Clinical Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, People's Republic of China
  3. 3State Key Laboratory for Structural Chemistry of Unstable and Stable Species, Institute of Chemistry Chinese Academy of Sciences, Beijing, People's Republic of China
  4. 4Hebei Key Laboratory of Medical-Industrial Integration Precision Medicine, College of Chemical Engineering, North China University of Science and Technology, Tangshan, People's Republic of China
  5. 5Senior Ward, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, People's Republic of China
  6. 6Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China
  7. 7Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China
  1. Correspondence to Professor Jihui Hao, Department of pancreatic cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; haojihui{at}tjmuch.com; Dr Jing Liu; piano_solo{at}163.com; Dr Chongbiao Huang; chhuang{at}tmu.edu.cn

Abstract

Objective The objective of this study is to improve the efficacy of CLDN18.2/CD3 bispecific T-cell engagers (BiTEs) as a promising immunotherapy against pancreatic ductal adenocarcinoma (PDAC).

Design Humanised hCD34+/hCD3e+, Trp53R172HKrasG12DPdx1-Cre (KPC), pancreas-specific Cldn18.2 knockout (KO), fibroblast-specific Fcgr1 KO and patient-derived xenograft/organoid mouse models were constructed. Flow cytometry, Masson staining, Cell Titer Glo assay, virtual drug screening, molecular docking and chromatin immunoprecipitation were conducted.

Results CLDN18.2 BiTEs effectively inhibited early tumour growth, but late-stage efficacy was significantly diminished. Mechanically, the Fc fragment of BiTEs interacted with CD64+ cancer-associated fibroblasts (CAFs) via activation of the SYK-VAV2-RhoA-ROCK-MLC2-MRTF-A-α-SMA/collagen-I pathway, which enhanced desmoplasia and limited late-stage infiltration of T cells. Molecular docking analysis found that vilanterol suppressed BiTEs-induced phosphorylation of VAV2 (Y172) in CD64+ CAFs and weakened desmoplasia. Additionally, decreased cyclic guanosine-adenosine monophosphate synthase/stimulator of interferon genes (STING) activity reduced proliferation of TCF-1+PD-1+ stem-like CD8+ T cells, which limited late-stage effects of BiTEs. Finally, vilanterol and the STING agonist synergistically boosted the efficacy of BiTEs by inhibiting the activation of CD64+ CAFs and enriching proliferation of stem-like CD8+ T cells, resulting in sustained anti-tumour activity.

Conclusion Vilanterol plus the STING agonist sensitised PDAC to CLDN18.2 BiTEs and augmented efficacy as a potential novel strategy.

  • pancreatic cancer
  • antibody targeted therapy
  • immunotherapy
  • fibrosis

Data availability statement

Data are available upon reasonable request.

https://doi.org/10.1136/gutjnl-2024-332371

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    Data availability statement

    Data are available upon reasonable request.

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    Footnotes

    • TZ, XH, JY and LL are joint first authors.

    • Contributors JH, JL and CH conceived and designed the experiments. TZ, XH, JY and LL performed most of the experiments. YX, WB, JW, YZ, XL, ZL, ZZ, BX, GM, YW, SG and JY performed some experiments. XW, TZ, HW, HS, XZ and CH provided the specimens. TZ analysed and discussed the data. CH revised the article. JH and JL supervised the entire project. JH is the guarantor.

    • Funding This work was supported by the National Key Research and Development Program of China(2021YFA1201100), the National Natural Science Foundation of China (grants 82030092 and 82072716), the Collaboration Program of Beijing Tianjin and Hebei (grant 22JCZXJC00120), the Clinical Young Specialist Construction Programs of Tianjin (grant TJSQNYXXR‐D2‐090), the Science and Technology Development Fund of Tianjin Education Commission for Higher Education (grant 2023KJ077), the Introduction of Talent and Doctoral Start‐Up Fund Project (grant B2210), the China Postdoctoral Science Foundation (grant 2023M742620) and the Science & Technology Development Fund of Tianjin Education Commission for Higher Education (2023KJ077), Tianjin Health Research Project (Grant No.TJ WJ2024QN016).

    • Competing interests None declared.

    • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.