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Int. J. Mol. Sci. 2017, 18(2), 270; doi:10.3390/ijms18020270

Expansion of T Cells with Interleukin-21 for Adoptive Immunotherapy of Murine Mammary Carcinoma

1
Department of Surgery, Virginia Commonwealth University Health System, Richmond, VA 23298, USA
2
Department of Biostatistics, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA
3
Division of Surgical Oncology, Virginia Commonwealth University Massey Cancer Center, Richmond, VA 23298, USA
*
Author to whom correspondence should be addressed.
Academic Editor: William Chi-shing Cho
Received: 25 November 2016 / Revised: 13 January 2017 / Accepted: 23 January 2017 / Published: 29 January 2017
(This article belongs to the Special Issue Targeting Immune Checkpoints and Immunotherapy)
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Abstract

We previously demonstrated that culturing antigen-sensitized draining lymph node (DLN) lymphocytes from BALB/c mice in interleukin (IL)-7/15 after activation with bryostatin/ionomycin (B/I) is superior to culture in IL-2 for expansion, differentiation to cluster of differentiation (CD)8+ cells and anti-tumor activity. We sought to determine whether the substitution or addition of IL-21 to culture had a similar effect. DLN lymphocytes were antigen-sensitized with 4T1 mammary carcinoma 10 days prior to harvest, activated with B/I, and expanded in culture for 7 days with either IL-2, IL-21, IL-2/21, IL-7/15, or IL-7/15/21. Cellular expansion, phenotype, interferon (IFN)-γ responses, and in vivo anti-tumor activity were compared. We found that T cells grown in IL7/15/21 demonstrated significantly greater lymphocyte expansion than IL-2, IL-21, IL-2/21, and IL-7/15 (38.4-fold vs. 5.5, 6.6, 9.5, and 23.9-fold, respectively). Of these expanded cells, IL-7/15/21 significantly expanded the greatest percentage of CD8+ cells (67.1% vs. 22.2%, 47.2%, 47.4%, and 55.3%, respectively), and the greatest number of T central memory cells (TCM) compared to IL-2, IL-21 and IL-2/21 (45.8% vs. 11.1%, 7.7%, and 12.1%, respectively). IL-21 and IL-2/21-expanded T cells preferentially differentiated into T naïve cells (TN) vs. those expanded in IL-2, IL-7/15 and IL-7/15/21 (27.6% and 23.2% vs. 1.7%, 4.5%, and 10.4%, respectively), and demonstrated the highest IFN-γ levels in vitro. In vivo adoptive immunotherapy (AIT) experiments demonstrated anti-tumor efficacy was equally effective using IL-2, IL-21, IL-2/21, IL-7/15 and IL-7/15/21-cultured lymphocytes vs. control or cyclophosphamide alone, even at lower doses or with greater initial size of tumor prior to treatment. View Full-Text
Keywords: adoptive immunotherapy; mammary carcinoma; IL-21; T lymphocytes adoptive immunotherapy; mammary carcinoma; IL-21; T lymphocytes
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MDPI and ACS Style

Zoon, C.K.; Wan, W.; Graham, L.; Bear, H.D. Expansion of T Cells with Interleukin-21 for Adoptive Immunotherapy of Murine Mammary Carcinoma. Int. J. Mol. Sci. 2017, 18, 270.

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