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Targeting cardiac fibrosis with engineered T cells

Author

Listed:
  • Haig Aghajanian

    (University of Pennsylvania
    University of Pennsylvania
    University of Pennsylvania)

  • Toru Kimura

    (University of Pennsylvania)

  • Joel G. Rurik

    (University of Pennsylvania
    University of Pennsylvania
    University of Pennsylvania)

  • Aidan S. Hancock

    (University of Pennsylvania
    University of Pennsylvania
    University of Pennsylvania)

  • Michael S. Leibowitz

    (University of Pennsylvania
    The Children’s Hospital of Philadelphia)

  • Li Li

    (University of Pennsylvania
    University of Pennsylvania
    University of Pennsylvania)

  • John Scholler

    (University of Pennsylvania)

  • James Monslow

    (University of Pennsylvania)

  • Albert Lo

    (University of Pennsylvania)

  • Wei Han

    (Hospital of the University of Pennsylvania)

  • Tao Wang

    (University of Pennsylvania)

  • Kenneth Bedi

    (University of Pennsylvania
    University of Pennsylvania)

  • Michael P. Morley

    (University of Pennsylvania
    University of Pennsylvania)

  • Ricardo A. Linares Saldana

    (University of Pennsylvania
    University of Pennsylvania
    University of Pennsylvania)

  • Nikhita A. Bolar

    (University of Pennsylvania
    University of Pennsylvania
    University of Pennsylvania)

  • Kendra McDaid

    (University of Pennsylvania)

  • Charles-Antoine Assenmacher

    (University of Pennsylvania)

  • Cheryl L. Smith

    (University of Pennsylvania
    University of Pennsylvania
    University of Pennsylvania)

  • Dagmar Wirth

    (Helmholtz Centre for Infection Research)

  • Carl H. June

    (University of Pennsylvania)

  • Kenneth B. Margulies

    (University of Pennsylvania
    University of Pennsylvania)

  • Rajan Jain

    (University of Pennsylvania
    University of Pennsylvania
    University of Pennsylvania
    University of Pennsylvania)

  • Ellen Puré

    (University of Pennsylvania)

  • Steven M. Albelda

    (University of Pennsylvania)

  • Jonathan A. Epstein

    (University of Pennsylvania
    University of Pennsylvania
    University of Pennsylvania
    University of Pennsylvania)

Abstract

Fibrosis is observed in nearly every form of myocardial disease1. Upon injury, cardiac fibroblasts in the heart begin to remodel the myocardium by depositing excess extracellular matrix, resulting in increased stiffness and reduced compliance of the tissue. Excessive cardiac fibrosis is an important factor in the progression of various forms of cardiac disease and heart failure2. However, clinical interventions and therapies that target fibrosis remain limited3. Here we demonstrate the efficacy of redirected T cell immunotherapy to specifically target pathological cardiac fibrosis in mice. We find that cardiac fibroblasts that express a xenogeneic antigen can be effectively targeted and ablated by adoptive transfer of antigen-specific CD8+ T cells. Through expression analysis of the gene signatures of cardiac fibroblasts obtained from healthy and diseased human hearts, we identify an endogenous target of cardiac fibroblasts—fibroblast activation protein. Adoptive transfer of T cells that express a chimeric antigen receptor against fibroblast activation protein results in a significant reduction in cardiac fibrosis and restoration of function after injury in mice. These results provide proof-of-principle for the development of immunotherapeutic drugs for the treatment of cardiac disease.

Suggested Citation

  • Haig Aghajanian & Toru Kimura & Joel G. Rurik & Aidan S. Hancock & Michael S. Leibowitz & Li Li & John Scholler & James Monslow & Albert Lo & Wei Han & Tao Wang & Kenneth Bedi & Michael P. Morley & Ri, 2019. "Targeting cardiac fibrosis with engineered T cells," Nature, Nature, vol. 573(7774), pages 430-433, September.
  • Handle: RePEc:nat:nature:v:573:y:2019:i:7774:d:10.1038_s41586-019-1546-z
    DOI: 10.1038/s41586-019-1546-z
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    Cited by:

    1. Lindo, Jason M. & Pineda-Torres, Mayra, 2021. "New Evidence on the Effects of Mandatory Waiting Periods for Abortion," Journal of Health Economics, Elsevier, vol. 80(C).
    2. Toshiyuki Ko & Seitaro Nomura & Shintaro Yamada & Kanna Fujita & Takanori Fujita & Masahiro Satoh & Chio Oka & Manami Katoh & Masamichi Ito & Mikako Katagiri & Tatsuro Sassa & Bo Zhang & Satoshi Hatsu, 2022. "Cardiac fibroblasts regulate the development of heart failure via Htra3-TGF-β-IGFBP7 axis," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    3. Zebin Xiao & Leslie Todd & Li Huang & Estela Noguera-Ortega & Zhen Lu & Lili Huang & Meghan Kopp & Yue Li & Nimisha Pattada & Wenqun Zhong & Wei Guo & John Scholler & Maria Liousia & Charles-Antoine A, 2023. "Desmoplastic stroma restricts T cell extravasation and mediates immune exclusion and immunosuppression in solid tumors," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    4. Yun Chang & Xuechao Cai & Ramizah Syahirah & Yuxing Yao & Yang Xu & Gyuhyung Jin & Vijesh J. Bhute & Sandra Torregrosa-Allen & Bennett D. Elzey & You-Yeon Won & Qing Deng & Xiaojun Lance Lian & Xiaogu, 2023. "CAR-neutrophil mediated delivery of tumor-microenvironment responsive nanodrugs for glioblastoma chemo-immunotherapy," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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