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Vγ9Vδ2 T cell-mediated recognition of human solid tumors. Potential for immunotherapy of hepatocellular and colorectal carcinomas

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Abstract

Introduction

Vγ9Vδ2 T lymphocytes are reported to participate in the anti-tumor immune surveillance in human. They are known to recognize phosphoantigens and molecules expressed on cells undergoing neoplasic transformation. In this study, we investigated phenotype and anti-tumor cytotoxicity of ex vivo expanded Vγ9Vδ2 T cells in view of adoptive immunotherapy.

Materials and Methods

Experiments were performed with peripheral blood samples from eleven patients [six colorectal carcinoma (CRC), four hepatocellular carcinoma (HCC), one sarcoma] and sixteen healthy donors.

Results/Discussion

Ex vivo expansion of Vγ9Vδ2 T cells could be achieved by a single dose of phosphoantigen, either bromohydrin pyrophosphate or zoledronate, and supported by exogenous IL-2. After 2 weeks, expanded Vγ9Vδ2 T lymphocytes acquired the effector memory phenotype CD45RA−CD45ROhighCD27−. They expressed NKG2D and CD161 and the proinflammatory CXCR3 and CCR5 chemokine receptors. Vγ9Vδ2 T cells displayed a strong lytic activity toward a broad panel of tumor cell lines or primary cultures. Interestingly, HCC and CRC primary cells could be lysed by autologous Vγ9Vδ2 T cells whereas autologous normal cells were not sensitive to the lysis. mAbs blocking assays demonstrated that TCR was the most important receptor involved in the lysis of tumor cells. However, NKG2D receptor could deliver a costimulatory signal enhancing the lysis of HCC and CRC tumors expressing MICA/B. Treatment of tumor cells by the mevalonate pathway inhibitor, zoledronate, enhanced the killing of both HCC and CRC. Expansion index of Vγ9Vδ2 T cells was in similar levels in healthy donors or in cancer patients and total expansion was suitable for adoptive immunotherapy.

Conclusion

These results provide a rationale for the clinical evaluation of Vγ9Vδ2 T lymphocytes in HCC and CRC.

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Abbreviations

IPP:

Isopentenyl pyrophosphate

BrHPP:

Bromohydrin pyrophosphate

HCC:

Hepatocellular carcinoma

CRC:

Colorectal carcinoma

RCC:

Renal cell carcinoma

HSP:

Heat shock protein

MICA/B:

MHC class I chain-related

ULBP:

UL16-binding protein

References

  1. Aldemir H, Prod’homme V, Dumaurier MJ, Retiere C, Poupon G, Cazareth J, Bihl F, Braud VM (2005) Cutting edge: lectin-like transcript 1 is a ligand for the CD161 receptor. J Immunol 175:7791–7795

    PubMed  CAS  Google Scholar 

  2. Barkholt L, Danielsson R, Calissendorff B, Svensson L, Malihi R, Remberger M, Uzunel M, Thorne A, Ringden O (2004) Indium-111-labelled donor-lymphocyte infusion by way of hepatic artery and radio-frequency ablation against liver metastases of renal and colon carcinoma after allogeneic hematopoietic stem-cell transplantation. Transplantation 78:697–703

    Article  PubMed  Google Scholar 

  3. Battistini L, Caccamo N, Borsellino G, Meraviglia S, Angelini DF, Dieli F, Cencioni MT, Salerno A (2005) Homing and memory patterns of human gammadelta T cells in physiopathological situations. Microbes Infect 7:510–517

    Article  PubMed  CAS  Google Scholar 

  4. Blattman JN, Greenberg PD (2004) Cancer immunotherapy: a treatment for the masses. Science 305:200–205

    Article  PubMed  CAS  Google Scholar 

  5. Bonneville M, Fournie JJ (2005) Sensing cell stress and transformation through Vgamma9Vdelta2 T cell-mediated recognition of the isoprenoid pathway metabolites. Microbes Infect 7:503–509

    Article  PubMed  CAS  Google Scholar 

  6. Bonneville M, Scotet E (2006) Human Vgamma9Vdelta2 T cells: promising new leads for immunotherapy of infections and tumors. Curr Opin Immunol 18:539–546

    Article  PubMed  CAS  Google Scholar 

  7. Choudhary A, Davodeau F, Moreau A, Peyrat MA, Bonneville M, Jotereau F (1995) Selective lysis of autologous tumor cells by recurrent gamma delta tumor-infiltrating lymphocytes from renal carcinoma. J Immunol 154:3932–3940

    PubMed  CAS  Google Scholar 

  8. Corvaisier M, Moreau-Aubry A, Diez E, Bennouna J, Mosnier JF, Scotet E, Bonneville M, Jotereau F (2005) V gamma 9V delta 2 T cell response to colon carcinoma cells. J Immunol 175:5481–5488

    PubMed  CAS  Google Scholar 

  9. Dieli F, Poccia F, Lipp M, Sireci G, Caccamo N, Di Sano C, Salerno A (2003) Differentiation of effector/memory Vdelta2 T cells and migratory routes in lymph nodes or inflammatory sites. J Exp Med 198:391–397

    Article  PubMed  CAS  Google Scholar 

  10. Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP, Royal RE, Kammula U, White DE, Mavroukakis SA, Rogers LJ, Gracia GJ, Jones SA, Mangiameli DP, Pelletier MM, Gea-Banacloche J, Robinson MR, Berman DM, Filie AC, Abati A, Rosenberg SA (2005) Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin Oncol 23:2346–2357

    Article  PubMed  CAS  Google Scholar 

  11. Exley M, Porcelli S, Furman M, Garcia J, Balk S (1998) CD161 (NKR-P1A) costimulation of CD1d-dependent activation of human T cells expressing invariant V alpha 24 J alpha Q T cell receptor alpha chains. J Exp Med 188:867–876

    Article  PubMed  CAS  Google Scholar 

  12. Favier B, Espinosa E, Tabiasco J, Dos Santos C, Bonneville M, Valitutti S, Fournie JJ (2003) Uncoupling between immunological synapse formation and functional outcome in human gamma delta T lymphocytes. J Immunol 171:5027–5033

    PubMed  CAS  Google Scholar 

  13. Ferrarini M, Ferrero E, Dagna L, Poggi A, Zocchi MR (2002) Human gammadelta T cells: a nonredundant system in the immune-surveillance against cancer. Trends Immunol 23:14–18

    Article  PubMed  CAS  Google Scholar 

  14. Girardi M (2006) Immunosurveillance and immunoregulation by gammadelta T cells. J Invest Dermatol 126:25–31

    Article  PubMed  CAS  Google Scholar 

  15. Glaise D, Ilyin GP, Loyer P, Cariou S, Bilodeau M, Lucas J, Puisieux A, Ozturk M, Guguen-Guillouzo C (1998) Cell cycle gene regulation in reversibly differentiated new human hepatoma cell lines. Cell Growth Differ 9:165–176

    PubMed  CAS  Google Scholar 

  16. Gober HJ, Kistowska M, Angman L, Jeno P, Mori L, De Libero G (2003) Human T cell receptor gammadelta cells recognize endogenous mevalonate metabolites in tumor cells. J Exp Med 197:163–168

    Article  PubMed  CAS  Google Scholar 

  17. Groh V, Rhinehart R, Randolph-Habecker J, Topp MS, Riddell SR, Spies T (2001) Costimulation of CD8alphabeta T cells by NKG2D via engagement by MIC induced on virus-infected cells. Nat Immunol 2:255–260

    Article  PubMed  CAS  Google Scholar 

  18. Hayday A, Tigelaar R (2003) Immunoregulation in the tissues by gammadelta T cells. Nat Rev Immunol 3:233–242

    Article  PubMed  CAS  Google Scholar 

  19. Kobayashi H, Tanaka Y, Yagi J, Osaka Y, Nakazawa H, Uchiyama T, Minato N, Toma H (2007) 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 56:469–476

    Article  PubMed  CAS  Google Scholar 

  20. Lanier LL (2005) NK cell recognition. Annu Rev Immunol 23:225–274

    Article  PubMed  CAS  Google Scholar 

  21. Morita CT, Jin C, Sarikonda G, Wang H (2007) Nonpeptide antigens, presentation mechanisms, and immunological memory of human Vgamma2Vdelta2 T cells: discriminating friend from foe through the recognition of prenyl pyrophosphate antigens. Immunol Rev 215:59–76

    Article  PubMed  CAS  Google Scholar 

  22. Pennington DJ, Silva-Santos B, Hayday AC (2005) Gammadelta T cell development—having the strength to get there. Curr Opin Immunol 17:108–115

    Article  PubMed  CAS  Google Scholar 

  23. Poggi A, Zocchi MR, Costa P, Ferrero E, Borsellino G, Placido R, Galgani S, Salvetti M, Gasperini C, Ristori G, Brosnan CF, Battistini L (1999) IL-12-mediated NKRP1A up-regulation and consequent enhancement of endothelial transmigration of V delta 2+ TCR gamma delta+ T lymphocytes from healthy donors and multiple sclerosis patients. J Immunol 162:4349–4354

    PubMed  CAS  Google Scholar 

  24. Raulet DH (2003) Roles of the NKG2D immunoreceptor and its ligands. Nat Rev Immunol 3:781–790

    Article  PubMed  CAS  Google Scholar 

  25. Rosen DB, Bettadapura J, Alsharifi M, Mathew PA, Warren HS, Lanier LL (2005) Cutting edge: lectin-like transcript-1 is a ligand for the inhibitory human NKR-P1A receptor. J Immunol 175:7796–7799

    PubMed  CAS  Google Scholar 

  26. Sato K, Kimura S, Segawa H, Yokota A, Matsumoto S, Kuroda J, Nogawa M, Yuasa T, Kiyono Y, Wada H, Maekawa T (2005) Cytotoxic effects of gammadelta T cells expanded ex vivo by a third generation bisphosphonate for cancer immunotherapy. Int J Cancer 116:94–99

    Article  PubMed  CAS  Google Scholar 

  27. Scotet E, Martinez LO, Grant E, Barbaras R, Jeno P, Guiraud M, Monsarrat B, Saulquin X, Maillet S, Esteve JP, Lopez F, Perret B, Collet X, Bonneville M, Champagne E (2005) Tumor recognition following Vgamma9Vdelta2 T cell receptor interactions with a surface F1-ATPase-related structure and apolipoprotein A-I. Immunity 22:71–80

    Article  PubMed  CAS  Google Scholar 

  28. Takayama T, Makuuchi M, Sekine T, Terui S, Shiraiwa H, Kosuge T, Yamazaki S, Hasegawa H, Suzuki K, Yamagata M, et al (1991) Distribution and therapeutic effect of intraarterially transferred tumor-infiltrating lymphocytes in hepatic malignancies. A preliminary report. Cancer 68:2391–2396

    CAS  Google Scholar 

  29. Thomas ML, Samant UC, Deshpande RK, Chiplunkar SV (2000) gammadelta T cells lyse autologous and allogenic oesophageal tumours: involvement of heat-shock proteins in the tumour cell lysis. Cancer Immunol Immunother 48:653–659

    Article  PubMed  CAS  Google Scholar 

  30. Viey E, Fromont G, Escudier B, Morel Y, Da Rocha S, Chouaib S, Caignard A (2005) Phosphostim-activated gamma delta T cells kill autologous metastatic renal cell carcinoma. J Immunol 174:1338–1347

    PubMed  CAS  Google Scholar 

  31. Vivier E, Tomasello E, Paul P (2002) Lymphocyte activation via NKG2D: towards a new paradigm in immune recognition? Curr Opin Immunol 14:306–311

    Article  PubMed  CAS  Google Scholar 

  32. Wadia P, Atre N, Pradhan T, Mistry R, Chiplunkar S (2005) Heat shock protein induced TCR gammadelta gene rearrangements in patients with oral cancer. Oral Oncol 41:175–182

    Article  PubMed  CAS  Google Scholar 

  33. Wang MH, Chen YQ, Gercken J, Ernst M, Bohle A, Flad HD, Ulmer AJ (1993) Specific activation of human peripheral blood gamma/delta + lymphocytes by sonicated antigens of Mycobacterium tuberculosis: role in vitro in killing human bladder carcinoma cell lines. Scand J Immunol 38:239–246

    Article  PubMed  CAS  Google Scholar 

  34. Wilhelm M, Kunzmann V, Eckstein S, Reimer P, Weissinger F, Ruediger T, Tony HP (2003) Gammadelta T cells for immune therapy of patients with lymphoid malignancies. Blood 102:200–206

    Article  PubMed  CAS  Google Scholar 

  35. Zhang H, Wang W, Zhang S, Huang W (2005) Comparison of the anti-tumor effects of various whole-body hyperthermia protocols: correlation with HSP 70 expression and composition of splenic lymphocytes. Immunol Invest 34:245–258

    Article  PubMed  CAS  Google Scholar 

  36. Zheng BJ, Ng SP, Chua DT, Sham JS, Kwong DL, Lam CK, Ng MH (2002) Peripheral gamma delta T-cell deficit in nasopharyngeal carcinoma. Int J Cancer 99:213–217

    Article  PubMed  CAS  Google Scholar 

  37. Zocchi MR, Ferrarini M, Rugarli C (1990) Selective lysis of the autologous tumor by delta TCS1+ gamma/delta+ tumor-infiltrating lymphocytes from human lung carcinomas. Eur J Immunol 20:2685–2689

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from the Comité Grand Ouest de la Ligue Contre le Cancer, the GIS de Thérapie Cellulaire de Rennes and the Institut National du Cancer (PL074). We thank E. Gougeon for technical assistance, D. Glaise and J. Le Seyec (INSERM U522, Rennes) for providing HCC cell lines and expert assistance in culture of normal hepatocytes, J-J. Fournié (INSERM U563, Toulouse) and Innate Pharma (Marseille) for providing BrHPP, V. Quillien (CRLCC, Rennes) for providing GB2 and GB3 glioblastoma primary cultures, and N. Rioux for anatomopathological examinations.

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Authors and Affiliations

  1. UPRES EA 3891, Faculté de Médecine de Rennes, 2 Avenue du Pr Léon Bernard, CS34317, 35043, Rennes cedex, France

    Francoise Bouet-Toussaint, Florian Cabillic, Olivier Toutirais, Matthieu Le Gallo, Noëlle Genetet & Véronique Catros

  2. Laboratoire de Cytogénétique et Biologie Cellulaire, CHU de Rennes, rue Henri Le Guilloux, 35033, Rennes cedex 9, France

    Francoise Bouet-Toussaint, Florian Cabillic, Cécile Thomas de la Pintière, Pascale Daniel & Véronique Catros

  3. Département de Chirurgie Viscérale, CHU de Rennes, 35033, Rennes cedex 9, France

    Bernard Meunier, Eric Dupont-Bierre & Karim Boudjema

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  1. Francoise Bouet-Toussaint
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Correspondence to Véronique Catros.

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Bouet-Toussaint, F., Cabillic, F., Toutirais, O. et al. Vγ9Vδ2 T cell-mediated recognition of human solid tumors. Potential for immunotherapy of hepatocellular and colorectal carcinomas. Cancer Immunol Immunother 57, 531–539 (2008). https://doi.org/10.1007/s00262-007-0391-3

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  • DOI: https://doi.org/10.1007/s00262-007-0391-3

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