Advertisement

Chinese Journal of Cancer Research

, Volume 24, Issue 2, pp 143–150 | Cite as

HER2-specific T lymphocytes kill both trastuzumab-resistant and trastuzumab-sensitive breast cell lines in vitro

  • Xiao-lin Lin
  • Xiao-li Wang
  • Bo Ma
  • Jun Jia
  • Ying Yan
  • Li-jun Di
  • Yan-hua Yuan
  • Feng-ling Wan
  • Yuan-li Lu
  • Xu Liang
  • Tao Shen
  • Jun RenEmail author
Original Article Breast Cancer

Abstract

Objective

Although the development of trastuzumab has improved the outlook for women with human epidermal growth factor receptor 2 (HER2)-positive breast cancer, the resistance to anti-HER2 therapy is a growing clinical dilemma. We aim to determine whether HER2-specific T cells generated from dendritic cells (DCs) modified with HER2 gene could effectively kill the HER2-positive breast cancer cells, especially the trastuzumab-resistant cells.

Methods

The peripheral blood mononuclear cells (PBMCs) from healthy donors, whose HLA haplotypes were compatible with the tumor cell lines, were transfected with reconstructive human adeno-association virus (rhAAV/HER2) to obtain the specific killing activities of T cells, and were evaluated by lactate dehydrogenase (LDH) releasing assay.

Results

Trastuzumab produced a significant inhibiting effect on SK-BR-3, the IC50 was 100ng /ml. MDA-MB-453 was resistant to trastuzumab even at a concentration of 10,000 ng/ml in vitro. HER2-specific T lymphocytes killed effectively SK-BR-3 [(69.86±13.41)%] and MDA-MB-453 [(78.36±10.68)%] at 40:1 (effector:target ratio, E:T), but had no significant cytotoxicity against HER2-negative breast cancer cell lines MDA-MB-231 or MCF-7 (less than 10%).

Conclusion

The study showed that HER2-specific T lymphocytes generated from DCs modified by rhAAV/HER2 could kill HER2-positive breast cancer cell lines in a HER2-dependent manner, and result in significantly high inhibition rates on the intrinsic trastuzumab-resistant cell line MDA-MB-453 and the tastuzumab-sensitive cell line SK-BR-3. These results imply that this immunotherapy might be a potential treatment to HER2-positive breast cancer.

Key words

HER2-positive breast cancer Trastuzumab-resistant Dendritic cells Immunotherapy Reconstructive human adeno-association virus 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin 2011;61:69–90.PubMedCrossRefGoogle Scholar
  2. 2.
    Slamon DJ, Clark GM, Wong SG, et al. Human breast cancer: correlation of relapse and survival with amplification of the HER2/neu oncogene. Science 1987;235:177–182.PubMedCrossRefGoogle Scholar
  3. 3.
    Slamon DJ, Godolphin W, Jones LA, et al. Studies of the HER2/neu proto-oncogene in human breast and ovarian cancer. Science 1989;244:707–712.PubMedCrossRefGoogle Scholar
  4. 4.
    Perou CM, Sorlie T, Eisen MB, et al. Molecular portraits of human breast tumours. Nature 2000;406:747–752.PubMedCrossRefGoogle Scholar
  5. 5.
    Hynes NE, Lane HA. ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer 2005;5:341–354.PubMedCrossRefGoogle Scholar
  6. 6.
    Kim R, Tanabe K, Uchida Y, et al. The role of HER2 oncoprotein in drug-sensitivity in breast cancer (review). Oncol Rep 2002;9:3–9.PubMedGoogle Scholar
  7. 7.
    Dowsett M. Overexpression of HER2 as a resistance mechanism to hormonal therapy for breast cancer. Endocr Relat Cancer 2001;8:191–195.PubMedCrossRefGoogle Scholar
  8. 8.
    Harbeck N. Breast cancer: Increasing therapy options for HER2-positive early breast cancer. Nat Rev Clin Oncol 2011;9:10–12.PubMedCrossRefGoogle Scholar
  9. 9.
    Mukohara T. Mechanisms of resistance to anti-human epidermal growth factor receptor 2 agents in breast cancer. Cancer Sci 2010;102:1–8.PubMedCrossRefGoogle Scholar
  10. 10.
    Jones KL, Buzdar AU. Evolving novel anti-HER2 strategies. Lancet Oncol 2009;10:1179–1187.PubMedCrossRefGoogle Scholar
  11. 11.
    Peoples GE, Goedegebuure PS, Smith R, et al. Breast and ovarian cancer-specific cytotoxic T lymphocytes recognize the same HER2/neu-derived peptide. Proc Natl Acad Sci USA 1995;92:432–436.PubMedCrossRefGoogle Scholar
  12. 12.
    Ladjemi MZ, Jacot W, Chardèt T et al. Anti-HER2 vaccines: new prospects for breast cancer therapy. Cancer Immunol Immunother 2010;59:1295–1312.PubMedCrossRefGoogle Scholar
  13. 13.
    Melief CJ. Cancer immunotherapy by dendritic cells. Immunity 2008;29:372–383.PubMedCrossRefGoogle Scholar
  14. 14.
    Ribas A. Genetically modified dendritic cells for cancer immunotherapy. Curr Gene Ther 2005;5:619–628.PubMedCrossRefGoogle Scholar
  15. 15.
    Daya S, Berns KI. Gene therapy using adeno-associated virus vectors. Clin Microbiol Rev 2008;21:583–593.PubMedCrossRefGoogle Scholar
  16. 16.
    Yu Y, Pilgrim P, Zhou W, et al. rAAV/HER2/neu loading of dendritic cells for a potent cellular-mediated MHC class I restricted immune response against ovarian cancer. Viral Immunol 2008;21:435–442.PubMedCrossRefGoogle Scholar
  17. 17.
    Mahadevan M, Liu Y, You C, et al. Generation of robust cytotoxic T lymphocytes against prostate specific antigen by transduction of dendritic cells using protein and recombinant adeno-associated virus. Cancer Immunol Immunother 2007;56:1615–1624.PubMedCrossRefGoogle Scholar
  18. 18.
    Wolff AC, Hammond ME, Schwartz JN, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol 2007;25:118–145.PubMedCrossRefGoogle Scholar
  19. 19.
    Charafe-Jauffret E, Ginestier C, Iovino F, et al. Breast cancer cell lines contain functional cancer stem cells with metastatic capacity and a distinct molecular signature. Cancer Res 2009;69:1302–1313.PubMedCrossRefGoogle Scholar
  20. 20.
    Korkaya H, Paulson A, Iovino F, et al. HER2 regulates the mammary stem/progenitor cell population driving tumorigenesis and invasion. Oncogene 2008;27:6120–6130.PubMedCrossRefGoogle Scholar
  21. 21.
    Nahta R, Esteva FJ. In vitro effects of trastuzumab and vinorelbine in trastuzumab-resistant breast cancer cells. Cancer Chemother Pharmacol 2004;53:186–190.PubMedCrossRefGoogle Scholar
  22. 22.
    Bedard PL, Cardoso F, Piccart-Gebhart MJ. Stemming resistance to HER2 targeted therapy. J Mammary Gland Biol Neoplasia 2009;14:55–66.PubMedCrossRefGoogle Scholar
  23. 23.
    Koninki K, Barok M, Tanner M, et al., Multiple molecular mechanisms underlying trastuzumab and lapatinib resistance in JIMT-1 breast cancer cells. Cancer Lett 2010;294:211–219.PubMedCrossRefGoogle Scholar
  24. 24.
    Ahmed N, Salsman VS, Kew Y, et al. HER2-specific T cells target primary glioblastoma stem cells and induce regression of autologous experimental tumors. Clin Cancer Res 2010;16:474–485.PubMedCrossRefGoogle Scholar
  25. 25.
    Sykulev Y, Joo M, Vturina I, et al. Evidence that a single peptide-MHC complex on a target cell can elicit a cytolytic T cell response. Immunity 1996;4:565–571.PubMedCrossRefGoogle Scholar
  26. 26.
    Unanue ER, Harding CV, Luescher IF, et al. Antigen-binding function of class II MHC molecules. Cold Spring Harb Symp Quant Biol 1989;54Pt 1:383–392.PubMedCrossRefGoogle Scholar
  27. 27.
    Inokuma M, dela Rosa C, Schmitt C, et al. Functional T cell responses to tumor antigens in breast cancer patients have a distinct phenotype and cytokine signature. J Immunol 2007;179:2627–2633.PubMedGoogle Scholar
  28. 28.
    Pinzon-Charry A, Maxwell T, McGuckin MA, et al. Spontaneous apoptosis of blood dendritic cells in patients with breast cancer. Breast Cancer Res 2006;8:R5.PubMedCrossRefGoogle Scholar
  29. 29.
    Zhang Y, Ma B, Zhou Y, et al. Dendritic cells fused with allogeneic breast cancer cell line induce tumor antigen-specific CTL responses against autologous breast cancer cells. Breast Cancer Res Treat 2007;105:277–286.PubMedCrossRefGoogle Scholar
  30. 30.
    Gabrilovich DI, Corak J, Ciernik IE, et al. Decreased antigen presentation by dendritic cells in patients with breast cancer. Clin Cancer Res 1997;3:483–490.PubMedGoogle Scholar
  31. 31.
    Lespagnard L, Gancberg D, Rouas G, et al. Tumor-infiltrating dendritic cells in adenocarcinomas of the breast: a study of 143 neoplasms with a correlation to usual prognostic factors and to clinical outcome. Int J Cancer 1999;84:309–314.PubMedCrossRefGoogle Scholar

Copyright information

© Chinese Anti-Cancer Association and Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • Xiao-lin Lin
    • 1
  • Xiao-li Wang
    • 1
  • Bo Ma
    • 1
  • Jun Jia
    • 1
  • Ying Yan
    • 1
  • Li-jun Di
    • 1
  • Yan-hua Yuan
    • 1
  • Feng-ling Wan
    • 1
  • Yuan-li Lu
    • 1
  • Xu Liang
    • 1
  • Tao Shen
    • 2
  • Jun Ren
    • 1
    Email author
  1. 1.Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Breast CancerPeking University Cancer Hospital & InstituteBeijingChina
  2. 2.Key Laboratory of Geriatrics, Beijing Hospital & Beijing Institute of GeriatricsMinistry of HealthBeijingChina

Personalised recommendations