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- 조회239
Biomaterials, Available online 20 March 2025, 123280 | https://doi.org/10.1016/j.biomaterials.2025.123280
Stromal Fibrin Shapes Immune Infiltration Landscape of Pancreatic Ductal Adenocarcinoma
Mazharul Karim 1 #, Md Mahedi Hasan 2 #, Seung Hyun Kim 3, Zulfikar Azam 1, Riajul Wahab 1, Tamanna Islam 2, Farzana Alam 4, Yun-Jae Kim 5, Dong-Jun Bae 5, Sourav Roy 6, Paul Grippo 7, Faraz Bishehsari 8, Jeong Uk Choi 3, Taslim A. Al-Hilal 1,2
1Department of Molecular Pharmaceutics, University of Utah, Salt Lake City, Utah, USA
2Department of Biomedical Engineering, University of Utah, Salt Lake City, Utah, USA
3College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea, 02453
4Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah, USA
5PrismCDX, Hwaseong-si, Gyeonggi-do, Korea
6Department of Biological Sciences, College of Sciences, University of Texas at El Paso, El Paso, Texas 79968
7Department of Medicine, University of Illinois at Chicago, Chicago, Illinois
8Department of Internal Medicine, Division of Gastroenterology, UTHealth Houston, Houston, TX 77030
#These authors contributed equally to this work
Corresponding author: Jeong Uk Choi, Taslim A. Al-Hilal
1Department of Molecular Pharmaceutics, University of Utah, Salt Lake City, Utah, USA
2Department of Biomedical Engineering, University of Utah, Salt Lake City, Utah, USA
3College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea, 02453
4Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah, USA
5PrismCDX, Hwaseong-si, Gyeonggi-do, Korea
6Department of Biological Sciences, College of Sciences, University of Texas at El Paso, El Paso, Texas 79968
7Department of Medicine, University of Illinois at Chicago, Chicago, Illinois
8Department of Internal Medicine, Division of Gastroenterology, UTHealth Houston, Houston, TX 77030
#These authors contributed equally to this work
Corresponding author: Jeong Uk Choi, Taslim A. Al-Hilal
Abstract
In pancreatic ductal adenocarcinoma (PDAC), in-situ coagulation creates a thrombotic, crosslinked fibrin (x-fibrin)-rich tumor stroma (FibTS), whose impact on immune cell behavior remains unclear. We aimed to elucidate how FibTS in PDAC regulates immune cell infiltration, polarization, and crosstalk that favors immunosuppressive microenvironment and tumor growth. We assessed the spatial distribution of immune cells by multiplex immunostaining of human PDAC tissues, along with novel bioengineering and mouse tumor models. We investigated how FibTS influences the infiltration of tumor-associated macrophage (TAM) and T-cell subtypes and identified two distinct variants of PDAC, fibrin-high (Fibhi) and fibrin-low (Fiblow). Our findings reveal that PDAC cells secrete fibrinogen and thrombin to form FibTS, which acts as a physical barrier and biochemical niche that restricts CD8+ T-cell and TAM penetration into the tumor. The FibTS impeded immune cell penetration from the tumor stroma into the tumor parenchyma. Selective inhibition of FibTS formation by genetic and pharmacological tools altered the infiltration patterns of CD8+ T-cells and TAMs, decelerating PDAC growth. This study demonstrates that the barrier function of FibTS is crucial for immune evasion, particularly against macrophage and T-cell activity, presenting a potential therapeutic strategy to reshape the immune landscape within PDAC and slow tumor progression.
논문정보
- Research article
- 2025년 03월 (BRIC 등록일 2025-03-25)
- 국내(교신)+국외 연구진
- 의약학 > 약학
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