title: Immune targeting of fibroblast activation protein triggers recognition of multipotent bone marrow stromal cells and cachexia.
abstract: 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.
authors.affiliation: Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. eric.tran@nih.gov
authors.forename: Eric
authors.initials: E
authors.lastname: Tran
authors.forename: Dhanalakshmi
authors.initials: D
authors.lastname: Chinnasamy
authors.forename: Zhiya
authors.initials: Z
authors.lastname: Yu
authors.forename: Richard A
authors.initials: RA
authors.lastname: Morgan
authors.forename: Chyi-Chia Richard
authors.initials: CC
authors.lastname: Lee
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Restifo
authors.forename: Steven A
authors.initials: SA
authors.lastname: Rosenberg
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology; D002100:Cachexia / Q000276:immunology* / Q000473:pathology; D045744:Cell Line, Tumor; D010450:Endopeptidases; D005260:Female; D005347:Fibroblasts / Q000276:immunology*; D018093:Gelatinases / Q000276:immunology*; D006801:Humans; D008297:Male; D008546:Melanoma, Experimental / Q000276:immunology; D008565:Membrane Proteins / Q000276:immunology*; D059630:Mesenchymal Stem Cells / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000276:immunology; D011946:Receptors, Antigen / Q000276:immunology; D012697:Serine Endopeptidases / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology; D000099167:Fibroblast Activation Protein Alpha
chemical_list: D000950:Antigens, Ly; D000951:Antigens, Neoplasm; D010450:Endopeptidases; D018093:Gelatinases; D008565:Membrane Proteins; D020796:Receptor, Platelet-Derived Growth Factor alpha; D011946:Receptors, Antigen; D012697:Serine Endopeptidases; D000099167:Fibroblast Activation Protein Alpha