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  • Title: Coculturing dendritic cells with zoledronate acid efficiently enhance the anti-tumor effects of cytokine-induced killer cells.
    Author: Su X, Zhang L, Jin L, Ye J, Guan Z, Chen R.
    Journal: J Clin Immunol; 2010 Sep; 30(5):766-74. PubMed ID: 20549316.
    Abstract:
    INTRODUCTION: Dendritic cells (DCs) have greater stimulating activity on innate and adaptive immunity following short-term sensitization with zoledronate acid (DCs(Zol)). We identified the phenotype, cytotoxicity, and mechanisms of killing of cytokine-induced killer (CIK) cells which were cocultured with DCs(Zol). METHODS: Adherent and nonadherent cells of peripheral blood mononuclear cell from myeloma patients were incubated for DCs and CIK cells. Then, the CIK cells were cocultured with DCs(Zol) (DCs(Zol)-CIK). Expression of markers for DCs(Zol)-CIK cells was measured using flow cytometry. Cytotoxicity was evaluated by against human myeloma cell lines and mechanisms of killing were tested by selectively blocking NKG2D receptor. The anti-tumor activity of these effector cells was further evaluated using a nude mice tumor model. RESULTS: gammadelta TCR expression of CIK cells significantly increased after coculture with immature or mature DCs(Zol) (iDCs/mDCs(Zol)-CIK) and these cells aggressively lysed myeloma cells compared with mDCs-CIK and zoledronate acid pulsed CIK cells (CIK(Zol); 50.8 +/- 7.9% and 48.2 +/- 4.7% versus 31.9 +/- 5.1% and 20.5 +/- 3.6%, effector versus target ratio was 60:1). Both alphabeta T and gammadelta T cells in the iDCs(Zol)-CIK cells performed the majority of lysis. The iDCs/mDCs(Zol)-CIK cells greatly increased NKG2D expression compared with mDCs-CIK and CIK(Zol) during culture (71.5 +/- 11.3% and 67.7 +/- 9.3% versus 51.3 +/- 6.2% and 47.1 +/- 5.7%). iDCs(Zol)-CIK cell-mediated lysis dropped 69.21% when the NKG2D receptor was blocked and the cytotoxicity correlated with NKG2D ligand-MICA expression on the target cells. In a human myeloma bearing nude mice model, iDCs(Zol)-CIK and mDCs(Zol)-CIK cells treatment groups obtained 75% and 62.5% long-term survival (>120 days) respectively, as compared with none of the control animals or 37.5% treated with mDCs-CIK cells. CONCLUSION: Large numbers of CIK cells with greater anti-tumor activities are rapidly generated by Zol-treated iDCs/mDCs. This strategy is worthy of further investigation to improve adoptive cell therapy against tumors.
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