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  2. Cell composition and expansion strategy can reduce the beneficial effect of AKT-inhibition on functionality of CD8+ T cells

Cell composition and expansion strategy can reduce the beneficial effect of AKT-inhibition on functionality of CD8+ T cells

  • Cancer Immunol Immunother. 2020 Nov;69(11):2259-2273. doi: 10.1007/s00262-020-02612-w.
Charlotte M Mousset 1 Willemijn Hobo 1 Aafke de Ligt 1 Sjoerd Baardman 1 Nicolaas P M Schaap 2 Joop H Jansen 1 Anniek B van der Waart 1 Harry Dolstra 3
Affiliations

Affiliations

  • 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.
  • 2 Department of Hematology, Radboud university medical center, Nijmegen, The Netherlands.
  • 3 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. Harry.Dolstra@radboudumc.nl.
Abstract

AKT-inhibition is a promising approach to improve T cell therapies; however, its effect on CD4+ T cells is insufficiently explored. Previously, we and Others showed that AKT-inhibition during ex vivo CD8+ 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 CD4+ T cells, during separate as well as total T cell expansions. Interestingly, ex vivo AKT-inhibition 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 CD8+ 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 CD8+ T cells is dependent on cell composition and expansion strategy, where presence of CD4+ T cells as well as polyclonal stimulation impede the favorable effect of AKT-inhibition.

Keywords

AKT; Memory; Polyfunctionality; T cell; Th1; Th2.

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