Abstract
BackgroundImmunotherapy 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.MethodsPurified 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.ResultsA 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).ConclusionsThese 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-0973-y) contains supplementary material, which is available to authorized users.
Highlights
Immunotherapy based on the adoptive transfer of gene modified T cells is an emerging approach for the induction of tumor-specific immune responses
We explored whether manipulating the length of CD3/ CD28 costimulation and/or the addition of IL-21 could enrich for the memory stem T cells (TSCM) population within T cells cultured under IL-7 and IL-15
Short CD3/CD28 costimulation enriches for memory stem T cells (TSCM) cultured with IL‐7/IL‐15 To assess whether the length of CD3/CD28 costimulation has an impact on the maintenance of the TSCM phenotype in vitro, naïve T cells were cultured with low doses of IL-7 and IL-15 and activated with magnetic beads coated with anti-CD3/anti-CD28
Summary
Immunotherapy based on the adoptive transfer of gene modified T cells is an emerging approach for the induction of tumor-specific immune responses. Adoptive T cell therapy (ACT) represents a highly promising strategy to treat cancer [1, 2] While this approach has been mostly based on the use of terminally differentiated effector T cells, recent studies indicate that. Alvarez‐Fernández et al J Transl Med (2016) 14:214 antitumor effect in vivo compared to other more differentiated T cell subsets [6, 8] All these features make TSCM a promising T cell subset candidate for ACT of cancer. Prolonged in vitro costimulation decrease the expression of memory markers substantially (e.g., CD62L, CCR7 or CD27) leading to a swift to more differentiated T cells [12, 13] For these reasons, identification of reproducible methods to generate and expand large numbers of TSCM for ACT of cancer remains a clinical priority
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