Generation of Antitumor Invariant Natural Killer T Cell Lines in Multiple Myeloma and Promotion of Their Functions via Lenalidomide: A Strategy for Immunotherapy

作者：Weihua Song, Hans J.J. van der Vliet, Yu-Tzu Tai, Rao Prabhala, Ruojie Wang, Klaus Podar, Laurence Catley, Masood A. Shammas, Kenneth C. Anderson, Steven P. Balk, Mark A. Exley, Nikhil C. Munshi · 发表于：Clinical Cancer Research · 年份：2008 · DOI：10.1158/1078-0432.ccr-07-5290 · 被引用次数：63 · 研究领域：Immune Cell Function and Interaction、Multiple Myeloma Research and Treatments、Immunotherapy and Immune Responses

PURPOSE: CD1d-restricted invariant natural killer T (iNKT) cells are important immunoregulatory cells in antitumor immune responses. However, the quantitative and qualitative defects of iNKT cells in advanced multiple myeloma hamper their antitumor effects. Therefore, the development of functional iNKT cells may provide a novel strategy for the immunotherapy in multiple myeloma. EXPERIMENTAL DESIGN: We activated and expanded iNKT cells from multiple myeloma patients with alpha-galactosylceramide (alpha-GalCer)-pulsed dendritic cells, characterized their antitumor effects by the cytokine production profile and cytotoxicity against multiple myeloma cells, and explored the effects of immunomodulatory drug lenalidomide on these iNKT cells. We also investigated the expression of CD1d by primary multiple myeloma cells and its function to activate iNKT cells. RESULTS: We established highly purified functional iNKT cell lines from newly diagnosed and advanced multiple myeloma patients. These CD1d-restricted iNKT cell lines produced high level of antitumor Th1 cytokine in response to alpha-GalCer-pulsed primary multiple myeloma cells, CD1d-transfected MM1S cell line, and dendritic cells. Moreover, iNKT cell lines displayed strong cytotoxicity against alpha-GalCer-pulsed primary multiple myeloma cells. Importantly, lenalidomide further augmented the Th1 polarization by iNKT cell lines via increased Th1 cytokine production and reduced Th2 cytokine production. We also showed that CD1d wa...