Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Immunotherapy targeting HER2 with genetically modified T cells eliminates tumor-initiating cells in osteosarcoma

Abstract

Despite radical surgery and multi-agent chemotherapy, less than one third of patients with recurrent or metastatic osteosarcoma (OS) survive. The limited efficacy of current therapeutic approaches to target tumor-initiating cells (TICs) may explain this dismal outcome. The purpose of this study was to assess the impact of modified T cells expressing a human epidermal growth factor receptor (HER2)-specific chimeric antigen receptor in the OS TIC compartment of human established cell lines. Using the sarcosphere formation assay, we found that OS TICs were resistant to increasing methotrexate concentrations. In contrast, HER2-specific T cells decreased markedly sarcosphere formation capacity and the ability to generate bone tumors in immunodeficient mice after orthotopic transplantation. In vivo, administration of HER2-specific T cells significantly reduced TICs in bulky tumors as judged by decreased sarcosphere forming efficiency in OS cells isolated from explanted tumors. We demonstrate that HER2-specific T cells target drug resistant TICs in established OS cell lines, suggesting that incorporating immunotherapy into current treatment strategies for OS has the potential to improve outcomes.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Purchase on Springer Link

Instant access to full article PDF

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Marina N, Gebhardt M, Teot L, Gorlick R . Biology and therapeutic advances for pediatric osteosarcoma. Oncologist 2004; 9: 422–441.

    Article  Google Scholar 

  2. Siclari VA, Qin L . Targeting the osteosarcoma cancer stem cell. J Orthop Surg Res 2010; 5: 78.

    Article  Google Scholar 

  3. Rosen JM, Jordan CT . The increasing complexity of the cancer stem cell paradigm. Science 2009; 324: 1670–1673.

    Article  CAS  Google Scholar 

  4. Adhikari AS, Agarwal N, Wood BM, Porretta C, Ruiz B, Pochampally RR et al. CD117 and Stro-1 identify osteosarcoma tumor-initiating cells associated with metastasis and drug resistance. Cancer Res 2010; 70: 4602–4612.

    Article  CAS  Google Scholar 

  5. Tirino V, Desiderio V, d′Aquino R, De Francesco F, Pirozzi G, Graziano A et al. Detection and characterization of CD133+ cancer stem cells in human solid tumours. PLoS One 2008; 3: e3469.

    Article  Google Scholar 

  6. Murase M, Kano M, Tsukahara T, Takahashi A, Torigoe T, Kawaguchi S et al. Side population cells have the characteristics of cancer stem-like cells/cancer-initiating cells in bone sarcomas. Br J Cancer 2009; 101: 1425–1432.

    Article  CAS  Google Scholar 

  7. Gibbs CP, Kukekov VG, Reith JD, Tchigrinova O, Suslov ON, Scott EW et al. Stem-like cells in bone sarcomas: implications for tumorigenesis. Neoplasia 2005; 7: 967–976.

    Article  CAS  Google Scholar 

  8. Fujii H, Honoki K, Tsujiuchi T, Kido A, Yoshitani K, Takakura Y . Sphere-forming stem-like cell populations with drug resistance in human sarcoma cell lines. Int J Oncol 2009; 34: 1381–1386.

    CAS  PubMed  Google Scholar 

  9. Lou N, Wang Y, Sun D, Zhao J, Gao Z . Isolation of stem-like cells from human MG-63 osteosarcoma cells using limiting dilution in combination with vincristine selection. Indian J Biochem Biophys 2010; 47: 340–347.

    CAS  PubMed  Google Scholar 

  10. Gorlick R, Huvos AG, Heller G, Aledo A, Beardsley GP, Healey JH et al. Expression of HER2/erbB-2 correlates with survival in osteosarcoma. J Clin Oncol 1999; 17: 2781–2788.

    Article  CAS  Google Scholar 

  11. Morris CD, Gorlick R, Huvos G, Heller G, Meyers PA, Healey JH . Human epidermal growth factor receptor 2 as a prognostic indicator in osteogenic sarcoma. Clin Orthop Relat Res 2001; 382: 59–65.

    Article  Google Scholar 

  12. Ahmed N, Salsman VS, Yvon E, Louis CU, Perlaky L, Wels WS et al. Immunotherapy for osteosarcoma: genetic modification of T cells overcomes low levels of tumor antigen expression. Mol Ther 2009; 17: 1779–1787.

    Article  CAS  Google Scholar 

  13. Rainusso N, Man TK, Lau CC, Hicks J, Shen JJ, Yu A et al. Identification and gene expression profiling of tumor-initiating cells isolated from human osteosarcoma cell lines in an orthotopic mouse model. Cancer Biol Ther 2011; 12: 278–287.

    Article  CAS  Google Scholar 

  14. Zhang M, Behbod F, Atkinson RL, Landis MD, Kittrell F, Edwards D et al. Identification of tumor-initiating cells in a p53-null mouse model of breast cancer. Cancer Res 2008; 68: 4674–4682.

    Article  CAS  Google Scholar 

  15. Gottschalk S, Edwards OL, Sili U, Huls MH, Goltsova T, Davis AR et al. Generating CTLs against the subdominant Epstein-Barr virus LMP1 antigen for the adoptive immunotherapy of EBV-associated malignancies. Blood 2003; 101: 1905–1912.

    Article  CAS  Google Scholar 

  16. Vera J, Savoldo B, Vigouroux S, Biagi E, Pule M, Rossig C et al. T lymphocytes redirected against the kappa light chain of human immunoglobulin efficiently kill mature B lymphocyte-derived malignant cells. Blood 2006; 108: 3890–3897.

    Article  CAS  Google Scholar 

  17. Jaffe N, Gorlick R . High-dose methotrexate in osteosarcoma: let the questions surcease-time for final acceptance. J Clin Oncol 2008; 26: 4365–4366.

    Article  CAS  Google Scholar 

  18. Wen YH, Koeppen H, Garcia R, Chiriboga L, Tarlow BD, Peters BA et al. Epidermal growth factor receptor in osteosarcoma: expression and mutational analysis. Hum Pathol 2007; 38: 1184–1191.

    Article  CAS  Google Scholar 

  19. Visvader JE, Lindeman GJ . Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat Rev Cancer 2008; 8: 755–768.

    Article  CAS  Google Scholar 

  20. Atkinson RL, Zhang M, Diagaradjane P, Peddibhotla S, Contreras A, Hilsenbeck SG et al. Thermal enhancement with optically activated gold nanoshells sensitizes breast cancer stem cells to radiation therapy. Sci Transl Med 2010; 2: 55ra79.

    Article  Google Scholar 

  21. Li X, Lewis MT, Huang J, Gutierrez C, Osborne CK, Wu MF et al. Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J Natl Cancer Inst 2008; 100: 672–679.

    Article  CAS  Google Scholar 

  22. Boman BM, Wicha MS . Cancer stem cells: a step toward the cure. J Clin Oncol 2008; 26: 2795–2799.

    Article  Google Scholar 

  23. West GW, Weichselbaum R, Little JB . Limited penetration of methotrexate into human osteosarcoma spheroids as a proposed model for solid tumor resistance to adjuvant chemotherapy. Cancer Res 1980; 40: 3665–3668.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This research was supported by The Children's Cancer Research Fund (NR and NA), the St Baldrick's Foundation (NR) and the Alex's Lemonade Stand Pediatric Cancer Foundation (NA) and the CPRIT Grant RP101335.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to N Ahmed.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on Cancer Gene Therapy website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rainusso, N., Brawley, V., Ghazi, A. et al. Immunotherapy targeting HER2 with genetically modified T cells eliminates tumor-initiating cells in osteosarcoma. Cancer Gene Ther 19, 212–217 (2012). https://doi.org/10.1038/cgt.2011.83

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/cgt.2011.83

Keywords

This article is cited by

Search

Quick links