Cell composition and expansion strategy can reduce the beneficial effect of AKT-inhibition on functionality of CD8 + T c
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ORIGINAL ARTICLE
Cell composition and expansion strategy can reduce the beneficial effect of AKT‑inhibition on functionality of CD8+ T cells Charlotte M. Mousset1 · Willemijn Hobo1 · Aafke de Ligt1 · Sjoerd Baardman1 · Nicolaas P. M. Schaap2 · Joop H. Jansen1 · Anniek B. van der Waart1 · Harry Dolstra1 Received: 28 November 2019 / Accepted: 15 May 2020 © The Author(s) 2020
Abstract AKT-inhibition is a promising approach to improve T cell therapies; however, its effect on C D4+ T cells is insufficiently + explored. Previously, we and others showed that AKT-inhibition during ex vivo C D8 T cell expansion facilitates the generation of polyfunctional T cells with stem cell memory-like traits. However, most therapeutic T cell products are generated from lymphocytes, containing CD4+ T cells that can affect CD8+ T cells dependent on the Th-subset. Here, we investigated the effect of AKT-inhibition on C D4+ T cells, during separate as well as total T cell expansions. Interestingly, ex vivo AKTinhibition preserved the early memory phenotype of CD4+ T cells based on higher CD62L, CXCR4 and CCR7 expression. However, in the presence of AKT-inhibition, Th-differentiation was skewed toward more Th2-associated at the expense of Th1-associated cells. Importantly, the favorable effect of AKT-inhibition on the functionality of C D8+ T cells drastically + diminished in the presence of CD4 T cells. Moreover, also the expansion method influenced the effect of AKT-inhibition on CD8+ T cells. These findings indicate that the effect of AKT-inhibition on C D8+ T cells is dependent on cell composition and expansion strategy, where presence of C D4+ T cells as well as polyclonal stimulation impede the favorable effect of AKT-inhibition. Keywords T cell · AKT · Memory · Polyfunctionality · Th1 · Th2
Introduction Adoptive transfer of tumor-reactive T lymphocytes has the potential to induce sustained clinical remission in patients with advanced cancer [1–3]. Clinical efficacy seems dependent amongst others on the infusion of tumor-reactive T Anniek B van der Waart and Harry Dolstra contributed equally to this work Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00262-020-02612-w) contains supplementary material, which is available to authorized users. * Harry Dolstra [email protected] 1
Department of Laboratory Medicine, Laboratory of Hematology, Radboud Institute of Molecular Life Sciences, Radboud university medical center, Geert Grooteplein Zuid 8, 6525 GA Nijmegen, The Netherlands
Department of Hematology, Radboud university medical center, Nijmegen, The Netherlands
2
cells with early memory-like characteristics [4–6]. Previously, we and others showed that transient pharmacological AKT-inhibition during ex vivo CD8+ T cell expansion that facilitates the generation of T cells with a stem cell memory (TSCM)-like phenotype [7–11]. Interestingly, AKT-inhibition during activation of C D8+ T cells allows proliferation, while preserving the
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