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Int. J. Mol. Sci. 2015, 16(4), 8744-8760;

Addition of Interleukin-21 for Expansion of T-Cells for Adoptive Immunotherapy of Murine Melanoma

Department of Surgery, Virginia Commonwealth University Health System, Richmond, VA 23298, USA
Department of Biostatistics, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA
Division of Surgical Oncology, Virginia Commonwealth University Massey Cancer Center, Richmond, VA 23298, USA
Author to whom correspondence should be addressed.
Academic Editor: Kamal D. Moudgil
Received: 9 March 2015 / Revised: 11 April 2015 / Accepted: 14 April 2015 / Published: 20 April 2015
(This article belongs to the Special Issue Mechanism of Action and Applications of Cytokines in Immunotherapy)
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We previously demonstrated that interleukin (IL)-7/15 was superior to IL-2 for expansion of T cells in vitro for adoptive immunotherapy. We sought to ascertain whether IL-21 would further improve yield and therapeutic efficacy of T cells in culture. Naïve T cell receptor (TcR) transgenic splenocytes or antigen-sensitized lymph node cells were harvested from PMEL-1 mice and exposed to bryostatin-1 and ionomycin (B/I) for 18 h. Cells were then cultured in IL-2, IL-21, IL-7/15 or IL-7/15/21 for six days. Harvested cells were analyzed by flow cytometry and used to treat C57Bl/6 mice injected intravenously with B16 melanoma. Lungs were harvested and metastases counted 14 days after treatment. Culturing lymphocytes in IL-7/15/21 increased expansion compared to IL-2 or IL-7/15. IL-21 and IL-7/15/21 increased CD8+ cells compared to IL-2 or IL-7/15. IL-21 preferentially expanded a CD8+CD44−CD62L+ T “naïve” population, whereas IL-7/15/21 increased CD8+CD44+CD62Lhigh central-memory T cells. T cells grown in IL-7/15/21 were more effective at reducing metastases than IL-2. The addition of IL-21 to IL-7/15 induced greater expansion of lymphocytes in culture and increased the yield of CD8+ T central-memory cells vs. IL-7/15 alone. This may have significant impact on future clinical trials of adoptive immunotherapy, particularly for generating adequate numbers of lymphocytes for treatment. View Full-Text
Keywords: adoptive immunotherapy; melanoma; IL-2; IL-7; IL-15; IL-21 adoptive immunotherapy; melanoma; IL-2; IL-7; IL-15; IL-21

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Zoon, C.K.; Wan, W.; Graham, L.; Bear, H.D. Addition of Interleukin-21 for Expansion of T-Cells for Adoptive Immunotherapy of Murine Melanoma. Int. J. Mol. Sci. 2015, 16, 8744-8760.

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