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

Publication ,  Journal Article
Fassnacht, M; Lee, J; Milazzo, C; Boczkowski, D; Su, Z; Nair, S; Gilboa, E
Published in: Clin Cancer Res
August 1, 2005

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.

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Published In

Clin Cancer Res

DOI

ISSN

1078-0432

Publication Date

August 1, 2005

Volume

11

Issue

15

Start / End Page

5566 / 5571

Location

United States

Related Subject Headings

  • Transfection
  • Transcription, Genetic
  • T-Lymphocytes, Cytotoxic
  • T-Lymphocytes
  • Serine Endopeptidases
  • Reverse Transcriptase Polymerase Chain Reaction
  • Recombinant Fusion Proteins
  • RNA, Messenger
  • Plasmids
  • Oncology & Carcinogenesis
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Fassnacht, M., Lee, J., Milazzo, C., Boczkowski, D., Su, Z., Nair, S., & Gilboa, E. (2005). Induction of CD4(+) and CD8(+) T-cell responses to the human stromal antigen, fibroblast activation protein: implication for cancer immunotherapy. Clin Cancer Res, 11(15), 5566–5571. https://doi.org/10.1158/1078-0432.CCR-05-0699
Fassnacht, Martin, Jaewoo Lee, Caterina Milazzo, David Boczkowski, Zhen Su, Smita Nair, and Eli Gilboa. “Induction of CD4(+) and CD8(+) T-cell responses to the human stromal antigen, fibroblast activation protein: implication for cancer immunotherapy.Clin Cancer Res 11, no. 15 (August 1, 2005): 5566–71. https://doi.org/10.1158/1078-0432.CCR-05-0699.
Fassnacht M, Lee J, Milazzo C, Boczkowski D, Su Z, Nair S, et al. Induction of CD4(+) and CD8(+) T-cell responses to the human stromal antigen, fibroblast activation protein: implication for cancer immunotherapy. Clin Cancer Res. 2005 Aug 1;11(15):5566–71.
Fassnacht, Martin, et al. “Induction of CD4(+) and CD8(+) T-cell responses to the human stromal antigen, fibroblast activation protein: implication for cancer immunotherapy.Clin Cancer Res, vol. 11, no. 15, Aug. 2005, pp. 5566–71. Pubmed, doi:10.1158/1078-0432.CCR-05-0699.
Fassnacht M, Lee J, Milazzo C, Boczkowski D, Su Z, Nair S, Gilboa E. Induction of CD4(+) and CD8(+) T-cell responses to the human stromal antigen, fibroblast activation protein: implication for cancer immunotherapy. Clin Cancer Res. 2005 Aug 1;11(15):5566–5571.

Published In

Clin Cancer Res

DOI

ISSN

1078-0432

Publication Date

August 1, 2005

Volume

11

Issue

15

Start / End Page

5566 / 5571

Location

United States

Related Subject Headings

  • Transfection
  • Transcription, Genetic
  • T-Lymphocytes, Cytotoxic
  • T-Lymphocytes
  • Serine Endopeptidases
  • Reverse Transcriptase Polymerase Chain Reaction
  • Recombinant Fusion Proteins
  • RNA, Messenger
  • Plasmids
  • Oncology & Carcinogenesis