Immunotherapy-based targeting of MSLN+ activated portal fibroblasts is a strategy for treatment of cholestatic liver fibrosis

Takahiro Nishio; Yukinori Koyama; Xiao Liu; Sara B Rosenthal; Gen Yamamoto; Hiroaki Fuji; Jacopo Baglieri; Na Li; Laura N Brenner; Keiko Iwaisako; Kojiro Taura; James S Hagood; Nicholas F LaRusso; Tapan K Bera; Ira Pastan; David A Brenner; Tatiana Kisseleva

doi:10.1073/pnas.2101270118

Immunotherapy-based targeting of MSLN⁺ activated portal fibroblasts is a strategy for treatment of cholestatic liver fibrosis

Proc Natl Acad Sci U S A. 2021 Jul 20;118(29):e2101270118. doi: 10.1073/pnas.2101270118.

Authors

Takahiro Nishio^{1

2}, Yukinori Koyama³, Xiao Liu^{1

2}, Sara B Rosenthal¹, Gen Yamamoto^{1

2}, Hiroaki Fuji^{1

2}, Jacopo Baglieri^{1

2}, Na Li^{1

2

4}, Laura N Brenner⁵, Keiko Iwaisako⁶, Kojiro Taura³, James S Hagood⁷, Nicholas F LaRusso⁸, Tapan K Bera⁹, Ira Pastan¹⁰, David A Brenner¹, Tatiana Kisseleva¹¹

Affiliations

¹ Department of Medicine, University of California San Diego Medical Center, La Jolla, CA 92161.
² Department of Surgery, University of California San Diego Medical Center, La Jolla, CA 92161.
³ Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, 606-8501, Japan.
⁴ Shanghai University of Medicine and Health Sciences, Shanghai 201318, China.
⁵ Pulmonary and Critical Care Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114.
⁶ Department of Medical Life Systems, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, 610-0394, Japan.
⁷ Program for Rare and Interstitial Lung Disease, Division of Pediatric Pulmonology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.
⁸ Center for Basic Research in Digestive Diseases, Division of Gastroenterology and Hepatology, Mayo Medical School, Clinic and Foundation, Rochester, MN 55905.
⁹ Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892.
¹⁰ Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892 pastani@mail.nih.gov tkisseleva@health.ucsd.edu.
¹¹ Department of Surgery, University of California San Diego Medical Center, La Jolla, CA 92161; pastani@mail.nih.gov tkisseleva@health.ucsd.edu.

Abstract

We investigated the role of mesothelin (Msln) and thymocyte differentiation antigen 1 (Thy1) in the activation of fibroblasts across multiple organs and demonstrated that Msln^-/- mice are protected from cholestatic fibrosis caused by Mdr2 (multidrug resistance gene 2) deficiency, bleomycin-induced lung fibrosis, and UUO (unilateral urinary obstruction)-induced kidney fibrosis. On the contrary, Thy1^-/- mice are more susceptible to fibrosis, suggesting that a Msln-Thy1 signaling complex is critical for tissue fibroblast activation. A similar mechanism was observed in human activated portal fibroblasts (aPFs). Targeting of human MSLN⁺ aPFs with two anti-MSLN immunotoxins killed fibroblasts engineered to express human mesothelin and reduced collagen deposition in livers of bile duct ligation (BDL)-injured mice. We provide evidence that antimesothelin-based therapy may be a strategy for treatment of parenchymal organ fibrosis.

Keywords: activated portal fibroblasts; cholestatic fibrosis; mesothelin.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Cholestasis / drug therapy*
Cholestasis / genetics
Cholestasis / immunology
Collagen / immunology
Fibroblasts / drug effects
Fibroblasts / immunology*
Humans
Immunotherapy*
Immunotoxins / administration & dosage
Liver Cirrhosis / drug therapy*
Liver Cirrhosis / genetics
Liver Cirrhosis / immunology
Mesothelin / genetics
Mesothelin / immunology
Mice
Thy-1 Antigens / genetics
Thy-1 Antigens / immunology

Substances

Immunotoxins
Msln protein, mouse
Thy-1 Antigens
Collagen
Mesothelin

Abstract

Publication types

MeSH terms

Substances

Grants and funding