Published online before print December 21, 2007

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(Journal of Leukocyte Biology. 2008;83:742-754.)
© 2008 by Society for Leukocyte Biology

Copulsing tumor antigen-pulsed dendritic cells with zoledronate efficiently enhance the expansion of tumor antigen-specific CD8+ T cells via V9 T cell activation

Masashi Takahara^*, Manami Miyai^*, Mai Tomiyama^*, Masato Mutou^*, Andrew J. Nicol and Mie Nieda^*,1

^* Medinet Medical Institute, Tokyo, Japan; and
Centre for Immune and Targeted Therapy, University of Queensland, Greenslopes Private Hospital, Brisbane, Australia

¹Correspondence: Medinet Medical Institute, Medinet Co., Ltd., 4-20-18 Seta, Setagaya-ku, Tokyo, 158-0095, Japan. E-mail: nieda{at}medinet-inc.co.jp

ABSTRACT

We demonstrate that V9 T cells activated by zoledronate can link innate and acquired immunity through crosstalk with dendritic cells (DCs) in a way that can amplify activation and proliferation of tumor antigen-specific CD8+ T cells. DCs pulsed with antigen alone or antigen plus zoledronate were used to stimulate the in vitro expansion of antigen-specific CD8+ T cells. MART-1-modified peptide (A27L peptide) and apoptotic HLA-A*0201-positive, MART-1-positive JCOCB tumor cell lines were used as tumor antigen sources. The percentage of A27L-specific CD8+ T cells within the responding lymphocytes on Day 7 when immature DCs (imDCs) were cultured in the presence of A27L peptide and 0.01 µM zoledronate was significantly higher (P=0.002, n=11) than that observed when imDCs were cultured with the lymphocytes in the presence of the A27L peptide alone. This enhancing effect of zoledronate was significantly reduced when T cells were depleted from responding lymphocytes (P=0.030, n=5), indicating that the effect is mediated mainly through V9 T cells activated by zoledronate-pulsed imDCs. When imDCs copulsed with zoledronate and apoptotic JCOCB tumor cell lines were used, the percentage of A27L-specific CD8+ T cells was higher than that observed using imDCs with the apoptotic JCOCB lines alone, suggesting that zoledronate treatment of imDCs enhances the cross-presentation ability of DCs. These findings suggest a potentially valuable role for V9 T cell activation for expanding antigen-specific CD8+T cells using DCs copulsed with tumor antigen and zoledronate in the design of vaccine therapies for malignancy.

Key Words: human • CTLs • adjuvants • aminobisphophonates