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

Journal of Experimental Medicine - Tập 210 Số 6 - Trang 1125-1135 - 2013
Eric Tran1,2, Dhanalakshmi Chinnasamy1,2, Zhiya Yu1,2, Richard A. Morgan1,2, Chyi‐Chia Richard Lee1,2, Nicholas P. Restifo1,2, Steven A. Rosenberg1,2
1Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 1 and 2
2Surgery Branch and Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892

Tóm tắt

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.

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Journal of Experimental Medicine

Tập 210 Số 6

1125-1135

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