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Desmoplastic stroma restricts T cell extravasation and mediates immune exclusion and immunosuppression in solid tumors

Author

Listed:
  • Zebin Xiao

    (University of Pennsylvania)

  • Leslie Todd

    (University of Pennsylvania)

  • Li Huang

    (University of Pennsylvania)

  • Estela Noguera-Ortega

    (University of Pennsylvania)

  • Zhen Lu

    (University of Pennsylvania)

  • Lili Huang

    (University of Pennsylvania)

  • Meghan Kopp

    (University of Pennsylvania)

  • Yue Li

    (University of Pennsylvania)

  • Nimisha Pattada

    (University of Pennsylvania)

  • Wenqun Zhong

    (University of Pennsylvania)

  • Wei Guo

    (University of Pennsylvania)

  • John Scholler

    (University of Pennsylvania)

  • Maria Liousia

    (University of Pennsylvania)

  • Charles-Antoine Assenmacher

    (University of Pennsylvania)

  • Carl H. June

    (University of Pennsylvania)

  • Steven M. Albelda

    (University of Pennsylvania)

  • Ellen Puré

    (University of Pennsylvania)

Abstract

The desmoplastic stroma in solid tumors presents a formidable challenge to immunotherapies that rely on endogenous or adoptively transferred T cells, however, the mechanisms are poorly understood. To define mechanisms involved, here we treat established desmoplastic pancreatic tumors with CAR T cells directed to fibroblast activation protein (FAP), an enzyme highly overexpressed on a subset of cancer-associated fibroblasts (CAFs). Depletion of FAP+ CAFs results in loss of the structural integrity of desmoplastic matrix. This renders these highly treatment-resistant cancers susceptible to subsequent treatment with a tumor antigen (mesothelin)-targeted CAR T cells and to anti-PD-1 antibody therapy. Mechanisms include overcoming stroma-dependent restriction of T cell extravasation and/or perivascular invasion, reversing immune exclusion, relieving T cell suppression, and altering the immune landscape by reducing myeloid cell accumulation and increasing endogenous CD8+ T cell and NK cell infiltration. These data provide strong rationale for combining tumor stroma- and malignant cell-targeted therapies to be tested in clinical trials.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40850-5
    DOI: 10.1038/s41467-023-40850-5
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    References listed on IDEAS

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    1. 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.
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