Skip to main content

Advertisement

SpringerLink
Log in

Anti-tumor effects of DNA vaccine targeting human fibroblast activation protein α by producing specific immune responses and altering tumor microenvironment in the 4T1 murine breast cancer model

  • Original Article
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Fibroblast activation protein α (FAPα) is a tumor stromal antigen overexpressed by cancer-associated fibroblasts (CAFs). CAFs are genetically more stable compared with the tumor cells and immunosuppressive components of the tumor microenvironment, rendering them excellent targets for cancer immunotherapy. DNA vaccines are widely applied due to their safety. To specifically destroy CAFs, we constructed and examined the immunogenicity and anti-tumor immune mechanism of a DNA vaccine expressing human FAPα. This vaccine successfully reduced 4T1 tumor growth through producing FAPα-specific cytotoxic T lymphocyte responses which could kill CAFs, and the decrease in FAPα-expressing CAFs resulted in markedly attenuated expression of collagen I and other stromal factors that benefit the tumor progression. Based on these results, a DNA vaccine targeting human FAPα may be an attractive and effective cancer immunotherapy strategy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Abbreviations

CAFs:

Cancer-associated fibroblasts

ECM:

Extracellular matrix

FAPα:

Fibroblast activation protein α

FGF-2:

Fibroblast growth factor-2

HGF:

Hematopoietic growth factor

PDGF:

Platelet-derived growth factor

SDF-1:

Stromal cell-derived factor-1

VEGFα:

Vascular endothelial growth factor alpha

References

  1. Siegel R, Ma J, Zou Z, Jemal A (2014) Cancer statistics, 2014. CA Cancer J Clin 64:9–29

    Article  PubMed  Google Scholar 

  2. Prud’homme GJ (2005) DNA vaccination against tumors. J Gene Med 7:3–17

    Article  PubMed  Google Scholar 

  3. Nguyen T, Urban J, Kalinski P (2014) Therapeutic cancer vaccines and combination immunotherapies involving vaccination. Immunotargets Ther 3:135–150

    CAS  Google Scholar 

  4. Scanlan MJ, Gure AO, Jungbluth AA, Old LJ, Chen Y-T (2002) Cancer/testis antigens: an expanding family of targets for cancer immunotherapy. Immunol Rev 188:22–32

    Article  CAS  PubMed  Google Scholar 

  5. Acharya PS, Zukas A, Chandan V, Katzenstein A-LA, Puré E (2006) Fibroblast activation protein: a serine protease expressed at the remodeling interface in idiopathic pulmonary fibrosis. Hum Pathol 37:352–360

    Article  CAS  PubMed  Google Scholar 

  6. Garin-Chesa P, Old LJ, Rettig WJ (1990) Cell surface glycoprotein of reactive stromal fibroblasts as a potential antibody target in human epithelial cancers. Proc Natl Acad Sci USA 87:7235–7239

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Niedermeyer J, Scanlan MJ, Garin-Chesa P, Daiber C, Fiebig HH, Old LJ, Rettig WJ, Schnapp A (1997) Mouse fibroblast activation protein: molecular cloning, alternative splicing and expression in the reactive stroma of epithelial cancers. Int J Cancer 71:383–389

    Article  CAS  PubMed  Google Scholar 

  8. Goldstein LA, Ghersi G, Piñeiro-Sánchez ML, Salamone M, Yeh Y, Flessate D, Chen W-T (1997) Molecular cloning of seprase: a serine integral membrane protease from human melanoma. Biochim Biophys Acta 1361:11–19

    Article  PubMed  Google Scholar 

  9. Rettig WJ, Garin-Chesa P, Healey JH, Su SL, Ozer HL, Schwab M, Albino AP, Old LJ (1993) Regulation and heteromeric structure of the fibroblast activation protein in normal and transformed cells of mesenchymal and neuroectodermal origin. Cancer Res 53:3327–3335

    CAS  PubMed  Google Scholar 

  10. Micke P (2004) Tumour-stroma interaction: Cancer-associated fibroblasts as novel targets in anti-cancer therapy? Lung Cancer 45:S163–S175

    Article  PubMed  Google Scholar 

  11. Östman A, Augsten M (2009) Cancer-associated fibroblasts and tumor growth—bystanders turning into key players. Curr Opin Genet Dev 19:67–73

    Article  PubMed  Google Scholar 

  12. Lee J, Fassnacht M, Nair S, Boczkowski D, Gilboa E (2005) Tumor immunotherapy targeting fibroblast activation protein, a product expressed in tumor-associated fibroblasts. Cancer Res 65:11156–11163

    Article  CAS  PubMed  Google Scholar 

  13. Cheng JD, Dunbrack RL, Valianou M, Rogatko A, Alpaugh RK, Weiner LM (2002) Promotion of tumor growth by murine fibroblast activation protein, a serine protease, in an animal model. Cancer Res 62:4767–4772

    CAS  PubMed  Google Scholar 

  14. Wen Y, Wang CT, Ma TT et al (2010) Immunotherapy targeting fibroblast activation protein inhibits tumor growth and increases survival in a murine colon cancer model. Cancer Sci 101:2325–2332

    Article  CAS  PubMed  Google Scholar 

  15. 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 11:5566–5571

    Article  CAS  PubMed  Google Scholar 

  16. Fearon DT (2014) The carcinoma-associated fibroblast expressing fibroblast activation protein and escape from immune surveillance. Cancer Immunol Res 2:187–193

    Article  CAS  PubMed  Google Scholar 

  17. Kalluri R, Zeisberg M (2006) Fibroblasts in cancer. Nat Rev Cancer 6:392–401

    Article  CAS  PubMed  Google Scholar 

  18. Ribatti D, Vacca A (2008) The role of microenvironment in tumor angiogenesis. Genes Nutr 3:29–34

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Joyce JA, Fearon DT (2015) T cell exclusion, immune privilege, and the tumor microenvironment. Science 348:74–80

    Article  CAS  PubMed  Google Scholar 

  20. Marincola FM, Jaffee EM, Hicklin DJ, Ferrone S (2000) Escape of human solid tumors from T-cell recognition: molecular mechanisms and functional significance. Adv Immunol 74:181–273

    Article  CAS  PubMed  Google Scholar 

  21. O’Connor DS, Schechner JS, Adida C, Mesri M, Rothermel AL, Li F, Nath AK, Pober JS, Altieri DC (2000) Control of apoptosis during angiogenesis by survivin expression in endothelial cells. Am J Pathol 156:393–398

    Article  PubMed  PubMed Central  Google Scholar 

  22. Gabrilovich DI, Chen HL, Girgis KR, Cunningham HT, Meny GM, Nadaf S, Kavanaugh D, Carbone DP (1996) Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat Med 2:1096–1103

    Article  CAS  PubMed  Google Scholar 

  23. Elgert KD, Alleva DG, Mullins DW (1998) Tumor-induced immune dysfunction: the macrophage connection. J Leukoc Biol 64:275–290

    CAS  PubMed  Google Scholar 

  24. Kraman M, Bambrough PJ, Arnold JN, Roberts EW, Magiera L, Jones JO, Gopinathan A, Tuveson DA, Fearon DT (2010) Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-α. Science 330:827–830

    Article  CAS  PubMed  Google Scholar 

  25. LeBleu VS (2015) Imaging the tumor microenvironment. Cancer J 21:174–178

    Article  PubMed  Google Scholar 

  26. Liu R, Li H, Liu L, Yu J, Ren X (2012) Fibroblast activation protein: a potential therapeutic target in cancer. Cancer Biol Ther 13:123–129

    Article  PubMed  Google Scholar 

  27. Cheng JD, Valianou M, Canutescu AA, Jaffe EK, Lee H-O, Wang H, Lai JH, Bachovchin WW, Weiner LM (2005) Abrogation of fibroblast activation protein enzymatic activity attenuates tumor growth. Mol Cancer Ther 4:351–360

    Article  CAS  PubMed  Google Scholar 

  28. Lladser A, Ljungberg K, Tufvesson H, Tazzari M, Roos A-K, Quest AF, Kiessling R (2010) Intradermal DNA electroporation induces survivin-specific CTLs, suppresses angiogenesis and confers protection against mouse melanoma. Cancer Immunol Immunother 59:81–92

    Article  CAS  PubMed  Google Scholar 

  29. Nagaraj S, Pisarev V, Kinarsky L, Sherman S, Muro-Cacho C, Altieri DC, Gabrilovich DI (2007) Dendritic cell-based full-length survivin vaccine in treatment of experimental tumors. J Immunother 30:169–179

    Article  CAS  PubMed  Google Scholar 

  30. Wang Y-Q, Zhang H-H, Liu C-L et al (2013) Enhancement of survivin-specific anti-tumor immunity by adenovirus prime protein-boost immunity strategy with DDA/MPL adjuvant in a murine melanoma model. Int Immunopharmacol 17:9–17

    Article  CAS  PubMed  Google Scholar 

  31. Wang Y, Liu C, Xia Q et al (2014) Antitumor effect of adenoviral vector prime protein boost immunity targeting the MUC1 VNTRs. Oncol Rep 31:1437–1444

    CAS  PubMed  Google Scholar 

  32. Zhang H, Wang Y, Liu C et al (2012) DNA and adenovirus tumor vaccine expressing truncated survivin generates specific immune responses and anti-tumor effects in a murine melanoma model. Cancer Immunol Immunother 61:1857–1867

    Article  CAS  PubMed  Google Scholar 

  33. You Q, Jiang C, Wu Y et al (2012) Subcutaneous administration of modified vaccinia virus ankara expressing an Ag85B-ESAT6 fusion protein, but not an adenovirus-based vaccine, protects mice against intravenous challenge with Mycobacterium tuberculosis. Scand J Immunol 75:77–84

    Article  CAS  PubMed  Google Scholar 

  34. Loeffler M, Kruger JA, Niethammer AG, Reisfeld RA (2006) Targeting tumor-associated fibroblasts improves cancer chemotherapy by increasing intratumoral drug uptake. J Clin Invest 116:1955–1962. doi:10.1172/JCI26532

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Liao D, Luo Y, Markowitz D, Xiang R, Reisfeld RA (2009) Cancer associated fibroblasts promote tumor growth and metastasis by modulating the tumor immune microenvironment in a 4T1 murine breast cancer model. PLoS One 4:e7965

    Article  PubMed  PubMed Central  Google Scholar 

  36. Henry LR, Lee H-O, Lee JS, Klein-Szanto A, Watts P, Ross EA, Chen W-T, Cheng JD (2007) Clinical implications of fibroblast activation protein in patients with colon cancer. Clin Cancer Res 13:1736–1741

    Article  CAS  PubMed  Google Scholar 

  37. Hofheinz R-D, Al-Batran S-E, Hartmann F et al (2003) Stromal antigen targeting by a humanised monoclonal antibody: an early phase II trial of sibrotuzumab in patients with metastatic colorectal cancer. Onkologie 26:44–48

    Article  CAS  PubMed  Google Scholar 

  38. Scott AM, Wiseman G, Welt S et al (2003) A phase I dose-escalation study of sibrotuzumab in patients with advanced or metastatic fibroblast activation protein-positive cancer. Clin Cancer Res 9:1639–1647

    CAS  PubMed  Google Scholar 

  39. Niedermeyer J, Kriz M, Hilberg F et al (2000) Targeted disruption of mouse fibroblast activation protein. Mol Cell Biol 20:1089–1094

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Park JE, Lenter MC, Zimmermann RN, Garin-Chesa P, Old LJ, Rettig WJ (1999) Fibroblast activation protein, a dual specificity serine protease expressed in reactive human tumor stromal fibroblasts. J Biol Chem 274:36505–36512

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by the National Natural Science Foundation of China (No. 31300765), Doctoral Program of Higher Education (New Teachers) (No. 20120061120025), Jilin Province Science and Technology Development Program (no. 20130522006JH), the National Science and Technology Major Project of the Ministry of Science and Technology of China (Nos. 2014ZX09304314-001, 2012ZX10001009-12) and the Fundamental Research Funds for the Central Universities (No. JCKY-QKJC03).

Author information

Authors and Affiliations

  1. National Engineering Laboratory for AIDS Vaccine, School of Life Science, Jilin University, No. 2699, Street Qianjin, Changchun, 130012, People’s Republic of China

    Qiu Xia, Fang-Fang Zhang, Fei Geng, Chen-Lu Liu, Ping Xu, Zhen-Zhen Lu, Bin Yu, Hui Wu, Jia-Xin Wu, Hai-Hong Zhang, Wei Kong & Xiang-Hui Yu

Authors
  1. Qiu Xia
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fang-Fang Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fei Geng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chen-Lu Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ping Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Zhen-Zhen Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Bin Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hui Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jia-Xin Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hai-Hong Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Wei Kong
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Xiang-Hui Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hai-Hong Zhang.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xia, Q., Zhang, FF., Geng, F. et al. Anti-tumor effects of DNA vaccine targeting human fibroblast activation protein α by producing specific immune responses and altering tumor microenvironment in the 4T1 murine breast cancer model. Cancer Immunol Immunother 65, 613–624 (2016). https://doi.org/10.1007/s00262-016-1827-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-016-1827-4

Keywords

Search

Navigation