한빛사논문
- 조회1,401
Young Eun Lee,1,2 Ga-Yeon Go,1 Eun-Young Koh,3 Han-Na Yoon,1 Minkoo Seo,4 Seung-Mo Hong,5 Ji Hye Jeong,3 Jin-Chul Kim,6 Duck Cho,7,8 Tae Sung Kim,2 Song Cheol Kim,9 Eunsung Jun,3,9 Mihue Jang1,10
1Medicinal Materials Research Center, Biomedical Research Division, Korea Institute of Science and Technology, Seoul, Korea (the Republic of)
2Department of Life Sciences, College of Life Sciences and Biotechnology, Korea University, Seoul, Korea (the Republic of)
3Department of Convergence Medicine, Asan Institute for Life Sciences, University of Ulsan College of Medicine and Asan Medical Center, Seoul, Korea (the Republic of)
4Corporate Research & Development Center, UCI therapeutics, Seoul, Korea (the Republic of)
5Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea (the Republic of)
6Natural Product Research Center, Institute of Natural Products, Korea Institute of Science and Technology, Gangneung, Korea (the Republic of)
7Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, Seoul, Korea (the Republic of)
8Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University, Seoul, Korea (the Republic of)
9Division of Hepato-Biliary and Pancreatic Surgery, Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea (the Republic of)
10KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul, Korea (the Republic of)
YEL, G-YG and E-YK contributed equally.
Correspondence to : Dr Mihue Jang; Professor Song Cheol Kim; Professor Eunsung Jun
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.
논문정보
- Research article
- 2023년 02월 (BRIC 등록일 2023-04-06)
- 국내 연구진
- 생명과학 > 유전자발현
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