A short CD3/CD28 costimulation combined with IL-21 enhance the generation of human memory stem T cells for adoptive immunotherapy. Issue 1 (December 2016)

• Record Type: Journal Article
• Authors: Alvarez-Fernández, C.; Escribà-Garcia, L.; Vidal, S.; Sierra, J.; Briones, J.
• Is Part Of: Journal of translational medicine. Volume 14:Issue 1(2016)
• Page Start: 1
• Page End: 10
• Publication Date: 2016-12
• Subjects: Immunotherapy -- IL-21 -- Memory stem T cell; Medicine, Experimental -- Periodicals; Human experimentation in medicine -- Periodicals; Therapeutics -- Periodicals; 615.50724
• DOI: 10.1186/s12967-016-0973-y
• Languages: English
• ISSNs: 1479-5876

Abstract

Abstract Background Immunotherapy based on the adoptive transfer of gene modified T cells is an emerging approach for the induction of tumor-specific immune responses. Memory stem T cells, due to their enhanced antitumor and self-renewal capacity, have become potential candidate for adoptive T cell therapy of cancer. Methods to generate memory stem T cells ex vivo rely on CD3/CD28 costimulation and the use of cytokines such as IL-7 and IL-15 during the entire culture period. However, a strong costimulation may induce differentiation of memory stem T cells to effector memory T cells. Here we show that manipulation of the length of the costimulation and addition of IL-21 enhance the ex vivo expansion of memory stem T cells. Methods Purified naïve T cells from healthy donors were cultured in the presence of anti-CD3/CD28 coated beads, IL-7, IL-15 and/or IL-21 (25 ng/ml). T cells phenotype from the different memory and effector subpopulations were analyzed by multiparametric flow cytometry. Results A short anti-CD3/CD28 costimulation of naïve T cells, combined with IL-7 and IL-15 significantly increased the frequencies of CD4+ and CD8+ memory stem T cells ex vivo, compared to a prolonged costimulation (34.6 ± 4.4 % vs 15.6 ± 4.24 % in CD4+ ; p = 0.008, and 20.5 ± 4.00 % vs 7.7 ± 2.53 % in CD8+ ; p = 0.02). Moreover, the addition of IL-21 to this condition further enhanced the enrichment and expansion of CD4+ and CD8+ memory stem T cells with an increase in the absolute numbers (0.7 × 106 ± 0.1 vs 0.26 × 106 ± 0.1 cells for CD4+ ; p = 0.002 and 1.1 × 106 ± 0.1 vs 0.27 × 106 ± 0.1 cells for CD8+ ; p = 0.0002; short + IL-21 vs long). Conclusions These new in vitro conditions increase the frequencies and expansion of memory stem T cells and may have relevant clinical implications for the generation of this memory T cell subset for adoptive cell therapy of patients with cancer.