Synergistic therapeutic combination with a CAF inhibitor enhances CAR-NK-mediated cytotoxicity via reduction of CAF-released IL-6

Young Eun Lee, Ga Yeon Go, Eun Young Koh, Han Na Yoon, Minkoo Seo, Seung Mo Hong, Ji Hye Jeong, Jin Chul Kim, Duck Cho, Tae Sung Kim, Song Cheol Kim, Eunsung Jun, Mihue Jang

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)

Abstract

Background Cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) contribute to an impaired functionality of natural killer (NK) cells that have emerged as a promising therapeutic modality. The interaction between CAFs and NK cells within the TME exerts major inhibitory effects on immune responses, indicating CAF-targeted therapies as potential targets for effective NK-mediated cancer killing. Methods To overcome CAF-induced NK dysfunction, we selected an antifibrotic drug, nintedanib, for synergistic therapeutic combination. To evaluate synergistic therapeutic efficacy, we established an in vitro 3D Capan2/patient-derived CAF spheroid model or in vivo mixed Capan2/CAF tumor xenograft model. The molecular mechanism of NK-mediated synergistic therapeutic combination with nintedanib was revealed through in vitro experiments. In vivo therapeutic combination efficacy was subsequently evaluated. Additionally, the expression score of target proteins was measured in patient-derived tumor sections by the immunohistochemical method. Results Nintedanib blocked the platelet-derived growth factor receptor β (PDGFRβ) signaling pathway and diminished the activation and growth of CAFs, markedly reducing CAF-secreted IL-6. Moreover, coadministration of nintedanib improved the mesothelin (MSLN) targeting chimeric antigen receptor-NK-mediated tumor killing abilities in CAF/tumor spheroids or a xenograft model. The synergistic combination resulted in intense NK infiltration in vivo. Nintedanib alone exerted no effects, whereas blockade of IL-6 trans-signaling ameliorated the function of NK cells. The combination of the expression of MSLN and the PDGFRβ + -CAF population area, a potential prognostic/therapeutic marker, was associated with inferior clinical outcomes. Conclusion Our strategy against PDGFRβ + -CAF-containing pancreatic cancer allows improvements in the therapy of pancreatic ductal adenocarcinoma.

Original languageEnglish
Article numbere006130
JournalJournal for ImmunoTherapy of Cancer
Volume11
Issue number2
DOIs
Publication statusPublished - 2023 Feb 27

Bibliographical note

Publisher Copyright:
© 2023 Author(s) (or their employer(s)). Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Keywords

  • Chimeric Antigen
  • Killer Cells
  • Natural
  • Receptors
  • Tumor Microenvironment

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

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