Large-scale expansion of γδ T cells and peptide-specific cytotoxic T cells using zoledronate for adoptive immunotherapy

Toshiaki Yoshikawa, Masashi Takahara, Mai Tomiyama, Mie Nieda, Ryuji Maekawa, Tetsuya Nakatsura

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)

Abstract

Specific cellular immunotherapy for cancer requires efficient generation and expansion of cytotoxic T lymphocytes (CTLs) that recognize tumor-associated antigens. However, it is difficult to isolate and expand functionally active T-cells ex vivo. In this study, we investigated the efficacy of a new method to induce expansion of antigen-specific CTLs for adoptive immunotherapy. We used tumor-associated antigen glypican-3 (GPC3)-derived peptide and cytomegalovirus (CMV)-derived peptide as antigens. Treatment of human peripheral blood mononuclear cells (PBMCs) with zoledronate is a method that enables large-scale γδ T-cell expansion. To induce expansion of γδ T cells and antigen-specific CTLs, the PBMCs of healthy volunteers or patients vaccinated with GPC3 peptide were cultured with both peptide and zoledronate for 14 days. The expansion of γδ T cells and peptide-specific CTLs from a few PBMCs using zoledronate yields cell numbers sufficient for adoptive transfer. The rate of increase of GPC3-specific CTLs was approximately 24- to 170,000-fold. These CD8+ cells, including CTLs, showed GPC3-specific cytotoxicity against SK-Hep-1/hGPC3 and T2 pulsed with GPC3 peptide, but not against SK-Hep-1/vec and T2 pulsed with human immunodeficiency virus peptide. On the other hand, CD8- cells, including γδ T cells, showed cytotoxicity against SK-Hep-1/hGPC3 and SK-Hep-1/vec, but did not show GPC3 specificity. Furthermore, adoptive cell transfer of CD8+ cells, CD8- cells, and total cells after expansion significantly inhibited tumor growth in an NOD/SCID mouse model. This study indicates that simultaneous expansion of γδ T cells and peptide-specific CTLs using zoledronate is useful for adoptive immunotherapy.

Original languageEnglish
Pages (from-to)1847-1856
Number of pages10
JournalInternational journal of oncology
Volume45
Issue number5
DOIs
Publication statusPublished - 2014 Nov 1
Externally publishedYes

Keywords

  • Adoptive cell transfer
  • Cytotoxic T lymphocyte
  • Glypican-3
  • Hepatocellular carcinoma
  • γδ T cell

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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