A short CD3/CD28 costimulation combined with IL-21 enhance the generation of human memory stem T cells for adoptive immunotherapy
Alvarez-Fernández, Carmen (Institut d'Investigació Biomèdica Sant Pau)
Escribà Garcia, Laura (Institut d'Investigació Biomèdica Sant Pau)
Vidal, Silvia (Institut d'Investigació Biomèdica Sant Pau)
Sierra, Jorge (Universitat Autònoma de Barcelona)
Briones Meijide, Javier (Universitat Autònoma de Barcelona)
Universitat Autònoma de Barcelona

Data:	2016
Resum:	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. 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. 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 × 10 6 ± 0. 1 vs 0. 26 × 10 6 ± 0. 1 cells for CD4 + ; p = 0. 002 and 1. 1 × 10 6 ± 0. 1 vs 0. 27 × 10 6 ± 0. 1 cells for CD8 + ; p = 0. 0002; short + IL-21 vs long). 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. The online version of this article (doi:10. 1186/s12967-016-0973-y) contains supplementary material, which is available to authorized users.
Ajuts:	Instituto de Salud Carlos III RD12/0036/0071 Agència de Gestió d'Ajuts Universitaris i de Recerca 2014/SGR-1281
Nota:	Altres ajuts: Fundació La Marató TV3
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Immunotherapy ; IL-21 ; Memory stem T cell
Publicat a:	Journal of translational medicine, Vol. 14 (july 2016) , ISSN 1479-5876

DOI: 10.1186/s12967-016-0973-y
PMID: 27435312

10 p, 2.1 MB

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