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.

  • Research Article
  • Published:

CDR3δ -grafted γ9δ2T cells mediate effective antitumor reactivity

Cellular & Molecular Immunology volume 9, pages 147–154 (2012)Cite this article

Abstract

Adoptive cell-transfer therapy (ACT) has been reported to suppress growing tumors and to overcome tumor escape in animal models. As a candidate ACT effector, γ9δ2T cells can be activated and expanded in vitro and in vivo and display strong antitumor activity against colorectal, lung, prostate, ovarian and renal cell carcinomas. However, it is difficult to obtain a large enough number of γδT cells to meet the need for immunotherapy that can overcome the cancer patients' immune suppressive tumor microenvironment. In previous studies, our lab confirmed that γ9δ2T cells recognized tumor cells via the CDR3δ region of the γδ-T-cell receptor (TCR). We constructed full-length human peripheral blood mononuclear cell (PBMC)-derived γ9 and δ2 chains in which the CDR3 region was replaced by an ovarian epithelial carcinoma (OEC)-derived CDR3. We transferred the CDR3δ-grafted γ9δ2TCR into peripheral blood lymphocytes (PBLs) to develop genetically modified γ9δ2T cells. In vitro studies have shown that these CDR3δ-grafted γ9δ2T cells can produce cytokines after stimulation with tumor cell extracts and exhibit cytotoxicity towards tumor cells, including human OEC and cervical adenocarcinoma. CDR3δ-grafted γ9δ2T cells adoptively transferred into nude mice bearing a human OEC cell line demonstrated significant antitumor effects. These results indicate that CDR3δ-grafted γ9δ2T cells might be candidates for clinical tumor immunotherapy.

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
Buy now

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

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Peng L, Shu SKrauss JC . Treatment of subcutaneous tumor with adoptively transferred T cells. Cell Immunol 1997; 178: 24–32.

    Article  CAS  PubMed  Google Scholar 

  2. Rosenberg SA, Spiess P, Lafreniere R . A new approach to the adoptive immunotherapy of cancer with tumor-infiltrating lymphocytes. Science 1986; 233: 1318–1321.

    Article  CAS  PubMed  Google Scholar 

  3. Plautz GE, Bukowski RM, Novick AC, Klein EA, Kursh ED, Olencki TE et al T-cell adoptive immunotherapy of metastatic renal cell carcinoma. Urology 1999; 54: 617–623; discussion 623–614.

    Article  CAS  PubMed  Google Scholar 

  4. Dudley ME, Wunderlich J, Nishimura MI, Yu D, Yang JC, Topalian SL et al Adoptive transfer of cloned melanoma-reactive T lymphocytes for the treatment of patients with metastatic melanoma. J Immunother 2001; 24: 363–373.

    Article  CAS  PubMed  Google Scholar 

  5. Dudley ME, Rosenberg SA . Adoptive-cell-transfer therapy for the treatment of patients with cancer. Nat Rev Cancer 2003; 3: 666–675.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Clay TM, Custer MC, Sachs J, Hwu P, Rosenberg SA, Nishimura MI . Efficient transfer of a tumor antigen-reactive TCR to human peripheral blood lymphocytes confers anti-tumor reactivity. J Immunol 1999; 163: 507–513.

    CAS  PubMed  Google Scholar 

  7. Morgan RA, Dudley ME, Yu YY, Zheng Z, Robbins PF, Theoret MR et al. High efficiency TCR gene transfer into primary human lymphocytes affords avid recognition of melanoma tumor antigen glycoprotein 100 and does not alter the recognition of autologous melanoma antigens. J Immunol 2003; 171: 3287–3295.

    Article  CAS  PubMed  Google Scholar 

  8. Hughes MS, Yu YY, Dudley ME, Zheng Z, Robbins PF, Li Y et al Transfer of a TCR gene derived from a patient with a marked antitumor response conveys highly active T-cell effector functions. Hum Gene Ther 2005; 16: 457–472.

    Article  CAS  PubMed  Google Scholar 

  9. Stanislawski T, Voss RH, Lotz C, Sadovnikova E, Willemsen RA, Kuball J et al. Circumventing tolerance to a human MDM2-derived tumor antigen by TCR gene transfer. Nat Immunol 2001; 2: 962–970.

    Article  CAS  PubMed  Google Scholar 

  10. Morgan RA, Dudley ME, Wunderlich JR, Hughes MS, Yang JC, Sherry RM et al. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 2006; 314: 126–129.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kessels HW, Wolkers MC, Schumacher TN . Adoptive transfer of T-cell immunity. Trends Immunol 2002; 23: 264–269.

    Article  CAS  PubMed  Google Scholar 

  12. Hayday AC . Gammadelta cells: a right time and a right place for a conserved third way of protection. Annu Rev Immunol 2000; 18: 975–1026.

    Article  CAS  PubMed  Google Scholar 

  13. Kabelitz D, Wesch D, He W . Perspectives of gammadelta T cells in tumor immunology. Cancer Res 2007; 67: 5–8.

    Article  CAS  PubMed  Google Scholar 

  14. Scotet E, Martinez LO, Grant E, Barbaras R, Jeno P, Guiraud M et al Tumor recognition following Vgamma9Vdelta2 T cell receptor interactions with a surface F1-ATPase-related structure and apolipoprotein A-I. Immunity 2005; 22: 71–80.

    Article  CAS  PubMed  Google Scholar 

  15. Chen H, He X, Wang Z, Wu D, Zhang H, Xu C et al. Identification of human T cell receptor gammadelta-recognized epitopes/proteins via CDR3delta peptide-based immunobiochemical strategy. J Biol Chem 2008; 283: 12528–12537.

    Article  CAS  PubMed  Google Scholar 

  16. Kang N, Zhou J, Zhang T, Wang L, Lu F, Cui Y et al. Adoptive immunotherapy of lung cancer with immobilized anti-TCRgammadelta antibody-expanded human gammadelta T-cells in peripheral blood. Cancer Biol Ther 2009; 8: 1540–1549.

    Article  CAS  PubMed  Google Scholar 

  17. Wilhelm M, Kunzmann V, Eckstein S, Reimer P, Weissinger F, Ruediger T et al. Gammadelta T cells for immune therapy of patients with lymphoid malignancies. Blood 2003; 102: 200–206.

    Article  CAS  PubMed  Google Scholar 

  18. Dieli F, Vermijlen D, Fulfaro F, Caccamo N, Meraviglia S, Cicero G et al. Targeting human gammadelta T cells with zoledronate and interleukin-2 for immunotherapy of hormone-refractory prostate cancer. Cancer Res 2007; 67: 7450–7457.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Wang Z, Zhang T, Hu H, Zhang H, Yang Z, Cui L et al. Targeting solid tumors via T cell receptor complementarity-determining region 3delta in an engineered antibody. Cancer Lett 2008; 272: 242–252.

    Article  CAS  PubMed  Google Scholar 

  20. Yuasa T, Sato K, Ashihara E, Takeuchi M, Maita S, Tsuchiya N et al Intravesical administration of gammadelta T cells successfully prevents the growth of bladder cancer in the murine model. Cancer Immunol Immunother 2009; 58: 493–502.

    Article  CAS  PubMed  Google Scholar 

  21. van der Veken LT, Hagedoorn RS, van Loenen MM, Willemze R, Falkenburg JH, Heemskerk MH . Alphabeta T-cell receptor engineered gammadelta T cells mediate effective antileukemic reactivity. Cancer Res 2006; 66: 3331–3337.

    Article  CAS  PubMed  Google Scholar 

  22. van der Veken LT, Coccoris M, Swart E, Falkenburg JH, Schumacher TN, Heemskerk MH . Alpha beta T cell receptor transfer to gamma delta T cells generates functional effector cells without mixed TCR dimers in vivo. J Immunol 2009; 182: 164–170.

    Article  CAS  PubMed  Google Scholar 

  23. Rock EP, Sibbald PR, Davis MM, Chien YH . CDR3 length in antigen-specific immune receptors. J Exp Med 1994; 179: 323–328.

    Article  CAS  PubMed  Google Scholar 

  24. Adams EJ, Strop P, Shin S, Chien YH, Garcia KC . An autonomous CDR3delta is sufficient for recognition of the nonclassical MHC class I molecules T10 and T22 by gammadelta T cells. Nat Immunol 2008; 9: 777–784.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Xu C, Zhang H, Hu H, He H, Wang Z, Xu Y, et al. Gammadelta T cells recognize tumor cells via CDR3delta region. Mol Immunol 2007; 44: 302–310.

    Article  CAS  PubMed  Google Scholar 

  26. Xi X, Guo Y, Chen H, Xu C, Zhang H, Hu H et al. Antigen specificity of gammadelta T cells depends primarily on the flanking sequences of CDR3delta. J Biol Chem 2009; 284: 27449–27455.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Bunnell BA, Muul LM, Donahue RE, Blaese RM, Morgan RA . High-efficiency retroviral-mediated gene transfer into human and nonhuman primate peripheral blood lymphocytes. Proc Natl Acad Sci USA 1995; 92: 7739–7743.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Corvaisier M, Moreau-Aubry A, Diez E, Bennouna J, Mosnier JF, Scotet E et al. V gamma 9V delta 2 T cell response to colon carcinoma cells. J Immunol 2005; 175: 5481–5488.

    Article  CAS  PubMed  Google Scholar 

  29. Kobayashi H, Tanaka Y, Yagi J, Osaka Y, Nakazawa H, Uchiyama T et al. Safety profile and anti-tumor effects of adoptive immunotherapy using gamma-delta T cells against advanced renal cell carcinoma: a pilot study. Cancer Immunol Immunother 2007; 56: 469–476.

    Article  CAS  PubMed  Google Scholar 

  30. Sato K, Kimura S, Segawa H, Yokota A, Matsumoto S, Kuroda J et al. Cytotoxic effects of gammadelta T cells expanded ex vivo by a third generation bisphosphonate for cancer immunotherapy. Int J Cancer 2005; 116: 94–99.

    Article  CAS  PubMed  Google Scholar 

  31. He X, Chen H, Wu D, Cui L, He W . Tandem-epitope peptide: a novel stimulator for gammadeltaT cells in tumor immunotherapy. Cancer Lett; 288: 86–93.

  32. Shin S, El-Diwany R, Schaffert S, Adams EJ, Garcia KC, Pereira P et al Antigen recognition determinants of gammadelta T cell receptors. Science 2005; 308: 252–255.

    Article  CAS  PubMed  Google Scholar 

  33. Dalton JE, Howell G, Pearson J, Scott P, Carding SR . Fas–Fas ligand interactions are essential for the binding to and killing of activated macrophages by gamma delta T cells. J Immunol 2004; 173: 3660–3667.

    Article  CAS  PubMed  Google Scholar 

  34. Nakata M, Smyth MJ, Norihisa Y, Kawasaki A, Shinkai Y, Okumura K et al. Constitutive expression of pore-forming protein in peripheral blood gamma/delta T cells: implication for their cytotoxic role in vivo. J Exp Med 1990; 172: 1877–1880.

    Article  CAS  PubMed  Google Scholar 

  35. Dieli F, Troye-Blomberg M, Ivanyi J, Fournie JJ, Krensky AM, Bonneville M et al. Granulysin-dependent killing of intracellular and extracellular Mycobacterium tuberculosis by Vgamma9/Vdelta2 T lymphocytes. J Infect Dis 2001; 184: 1082–1085.

    Article  CAS  PubMed  Google Scholar 

  36. Christmas SE, Meager A . Production of interferon-gamma and tumour necrosis factor-alpha by human T-cell clones expressing different forms of the gamma delta receptor. Immunology 1990; 71: 486–492.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Poehlein CH, Hu HM, Yamada J, Assmann I, Alvord WG, Urba WJ et al. TNF plays an essential role in tumor regression after adoptive transfer of perforin/IFN-gamma double knockout effector T cells. J Immunol 2003; 170: 2004–2013.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work is supported by two grants, no. 2006AA02Z480 and no. 2007AA021109, from the National Program for Biomedical Hightech, the Ministry of Science and Technology, China. The authors gratefully acknowledged Dr Keng Shen for providing tumor cell line SKOV3 and HO8910.

Author information

Authors and Affiliations

  1. Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine, Peking Union Medical College, Beijing, China

    Hui Zhao, Xueyan Xi, Lianxian Cui & Wei He

Authors
  1. Hui Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xueyan Xi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lianxian Cui
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wei He
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Wei He.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhao, H., Xi, X., Cui, L. et al. CDR3δ -grafted γ9δ2T cells mediate effective antitumor reactivity. Cell Mol Immunol 9, 147–154 (2012). https://doi.org/10.1038/cmi.2011.28

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/cmi.2011.28

Keywords

This article is cited by

Search

Advanced search

Quick links