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

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)1065-1068
Number of pages4
JournalJournal of Experimental Medicine
Volume210
Issue number6
DOIs
StatePublished - Jun 2013

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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