Lee, Young Eun Ga-yeon Go Koh, Eun-Young Yoon Han-Na Seo, Minkoo Hong, Seung-Mo Jeong, Ji-Hye Kim, Jin-Chul Choi, Duck Kim, Tae Sung Kim, Song-Cheol Jun, Eunsung JANG, MI HUE 2024-01-12T02:32:11Z 2024-01-12T02:32:11Z 2023-03-15 2023-02 2051-1426 https://pubs.kist.re.kr/handle/201004/75801 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. English BioMed Central Synergistic therapeutic combination with a CAF inhibitor enhances CAR-NK-mediated cytotoxicity via reduction of CAF-released IL-6 Article 10.1136/jitc-2022-006130 1 Journal for ImmunoTherapy of Cancer, v.11, no.2 Journal for ImmunoTherapy of Cancer 11 2 Y scie scopus 000942521200001 2-s2.0-85148969089 Oncology Immunology Oncology Immunology Article CELL DYSFUNCTION FIBROBLASTS ACTIVATION MESOTHELIN IMMUNOTHERAPY SOMATOSTATIN Receptors Chimeric Antigen Killer Cells Natural Tumor Microenvironment