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Immune targeting of fibroblast activation protein triggers recognition of multipotent bone marrow stromal cells and cachexia

Tran, Eric ; Chinnasamy, Dhanalakshmi ; Yu, Zhiya ; Morgan, Richard A ; Lee, Chyi-Chia Richard ; Restifo, Nicholas P ; Rosenberg, Steven A

The Journal of experimental medicine, 2013-06, Vol.210 (6), p.1125-1135 [Periódico revisado por pares]

United States: The Rockefeller University Press

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Título:
Immune targeting of fibroblast activation protein triggers recognition of multipotent bone marrow stromal cells and cachexia
Autor: Tran, Eric ; Chinnasamy, Dhanalakshmi ; Yu, Zhiya ; Morgan, Richard A ; Lee, Chyi-Chia Richard ; Restifo, Nicholas P ; Rosenberg, Steven A
Assuntos: Animals ; Antigens, Ly - immunology ; Antigens, Neoplasm - immunology ; Brief Definitive Report ; Cachexia - immunology ; Cachexia - pathology ; Cell Line, Tumor ; Female ; Fibroblasts - immunology ; Gelatinases - immunology ; Humans ; Male ; Melanoma, Experimental - immunology ; Membrane Proteins - immunology ; Mesenchymal Stromal Cells - immunology ; Mice ; Mice, Inbred BALB C ; Receptor, Platelet-Derived Growth Factor alpha - immunology ; Receptors, Antigen - immunology ; Serine Endopeptidases - immunology ; T-Lymphocytes - immunology
É parte de: The Journal of experimental medicine, 2013-06, Vol.210 (6), p.1125-1135
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Descrição: Fibroblast activation protein (FAP) is a candidate universal target antigen because it has been reported to be selectively expressed in nearly all solid tumors by a subset of immunosuppressive tumor stromal fibroblasts. We verified that 18/18 human tumors of various histologies contained pronounced stromal elements staining strongly for FAP, and hypothesized that targeting tumor stroma with FAP-reactive T cells would inhibit tumor growth in cancer-bearing hosts. T cells genetically engineered with FAP-reactive chimeric antigen receptors (CARs) specifically degranulated and produced effector cytokines upon stimulation with FAP or FAP-expressing cell lines. However, adoptive transfer of FAP-reactive T cells into mice bearing a variety of subcutaneous tumors mediated limited antitumor effects and induced significant cachexia and lethal bone toxicities in two mouse strains. We found that FAP was robustly expressed on PDGFR-α(+), Sca-1(+) multipotent bone marrow stromal cells (BMSCs) in mice, as well as on well-characterized, clinical-grade multipotent human BMSCs. Accordingly, both mouse and human multipotent BMSCs were recognized by FAP-reactive T cells. The lethal bone toxicity and cachexia observed after cell-based immunotherapy targeting FAP cautions against its use as a universal target. Moreover, the expression of FAP by multipotent BMSCs may point toward the cellular origins of tumor stromal fibroblasts.
Editor: United States: The Rockefeller University Press
Idioma: Inglês

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Immune targeting of fibroblast activation protein triggers recognition of multipotent bone marrow stromal cells and cachexia

Tran, Eric ; Chinnasamy, Dhanalakshmi ; Yu, Zhiya ; Morgan, Richard A ; Lee, Chyi-Chia Richard ; Restifo, Nicholas P ; Rosenberg, Steven A

United States: The Rockefeller University Press

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