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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

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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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