Induction of CD4+ and CD8+ T-cell responses to the human stromal antigen, fibroblast activation protein: Implication for cancer immunotherapy

Martin Fassnacht, Jaewoo Lee, Caterina Milazzo, David Boczkowski, Zhen Su, Smita Nair, Eli Gilboa

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

Purpose: The propensity of tumor cells to escape immune elimination could limit, if not defeat, the long-term benefits of effective immunotherapeutic protocols. Immunologic targeting of tumor stroma could significantly reduce the ability of tumors to evade immune elimination. Murine studies have shown that inducing immunity against angiogenesis-associated products engenders potent antitumor immunity without significant pathology. It is, however, not known whether T cells corresponding to stromal products are present in humans. In this study, we describe a method to screen for human stromal products that have not triggered significant tolerance and could therefore serve as candidate antigens for cancer immunotherapy. Experimental Design: To identify candidates for human stromal antigens, we used an in vitro - screening method to determine whether dendritic cells transfected with mRNA encoding products, which are overexpressed in the tumor stroma, are capable of stimulating cytotoxic CD8+ (CTL) responses from human peripheral blood mononuclear cells. Results: CTL responses could be consistently generated against fibroblast activation protein (FAP) but not against matrix metalloproteinase-9 (MMP-9) or MMP-14. To enhance the immunogenicity of the mRNA-translated FAP product, a lysosomal targeting signal derived from lysosome-associated membrane protein-1 (LAMP-1) was fused to the COOH terminus of FAP to redirect the translated product into the class II presentation pathway. Dendritic cells transfected with mRNA encoding the FAP-LAMP fusion product stimulated enhanced CD4+ and CD8+ T-cell responses. Conclusion: This study identifies FAP, a protease preferentially expressed in tumor-associated fibroblasts, as a candidate human stromal antigen to target in the setting of cancer immunotherapy, and shows that differential expression of stromal products is not a sufficient criteria to indicate its immunogenicity in a vaccination setting.

Original languageEnglish
Pages (from-to)5566-5571
Number of pages6
JournalClinical Cancer Research
Volume11
Issue number15
DOIs
StatePublished - Aug 1 2005
Externally publishedYes

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Immunotherapy
Fibroblasts
T-Lymphocytes
Antigens
Lysosome-Associated Membrane Glycoproteins
Neoplasms
Proteins
Dendritic Cells
Messenger RNA
Immunity
Matrix Metalloproteinase 9
Matrix Metalloproteinases
Blood Cells
Vaccination
Peptide Hydrolases
Research Design
Pathology

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Induction of CD4+ and CD8+ T-cell responses to the human stromal antigen, fibroblast activation protein : Implication for cancer immunotherapy. / Fassnacht, Martin; Lee, Jaewoo; Milazzo, Caterina; Boczkowski, David; Su, Zhen; Nair, Smita; Gilboa, Eli.

In: Clinical Cancer Research, Vol. 11, No. 15, 01.08.2005, p. 5566-5571.

Research output: Contribution to journalArticle

Fassnacht, Martin ; Lee, Jaewoo ; Milazzo, Caterina ; Boczkowski, David ; Su, Zhen ; Nair, Smita ; Gilboa, Eli. / Induction of CD4+ and CD8+ T-cell responses to the human stromal antigen, fibroblast activation protein : Implication for cancer immunotherapy. In: Clinical Cancer Research. 2005 ; Vol. 11, No. 15. pp. 5566-5571.
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