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Ex vivo AKT-inhibition facilitates generation of polyfunctional stem cell memory-like CD8+ T cells for adoptive immunotherapy

Mousset CM, Hobo W, Ji Y, Fredrix H, De Giorgi V, Allison RD, Kester MGD, Falkenburg JHF, Schaap NPM, Jansen JH, Gattinoni L, Dolstra H, Van Der Waart AB (2018)

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Publication Type: Journal article

Publication year: 2018

Journal

Book Volume: 7

Article Number: e1488565

Journal Issue: 10

DOI: 10.1080/2162402X.2018.1488565

Abstract

Adoptive T cell therapy has shown clinical potential for patients with cancer, though effective treatment is dependent on longevity and potency of the exploited tumor-reactive T cells. Previously, we showed that ex vivo inhibition of AKT using the research compound Akt-inhibitor VIII retained differentiation and improved functionality of minor histocompatibility antigen (MiHA)-specific CD8⁺ T cells. Here, we compared a panel of clinically applicable AKT-inhibitors with an allosteric or adenosine triphosphate-competitive mode of action. We analyzed phenotype, functionality, metabolism and transcriptome of AKT-inhibited CD8⁺ T cells using different T cell activation models. Most inhibitors facilitated T cell expansion while preserving an early memory phenotype, reflected by maintenance of CD62L, CCR7 and CXCR4 expression. Moreover, transcriptome profiling revealed that AKT-inhibited CD8⁺ T cells clustered closely to naturally occurring stem cell-memory CD8⁺ T cells, while control T cells resembled effector-memory T cells. Interestingly, AKT-inhibited CD8⁺ T cells showed enrichment of hypoxia-associated genes, which was consistent with enhanced glycolytic function. Notably, AKT-inhibition during MiHA-specific CD8⁺ T cell priming uncoupled preservation of early memory differentiation from ex vivo expansion. Furthermore, AKT-inhibited MiHA-specific CD8⁺ T cells showed increased polyfunctionality with co-secretion of IFN-γ and IL-2 upon antigen recall. Together, these data demonstrate that AKT-inhibitors with different modality of action promote the ex vivo generation of stem cell memory-like CD8⁺ T cells with a unique metabolic profile and retained polyfunctionality. Akt-inhibitor VIII and GDC-0068 outperformed other inhibitors, and are therefore promising candidates for ex vivo generation of superior tumor-reactive T cells for adoptive immunotherapy in cancer patients.

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How to cite

APA:

Mousset, C.M., Hobo, W., Ji, Y., Fredrix, H., De Giorgi, V., Allison, R.D.,... Van Der Waart, A.B. (2018). Ex vivo AKT-inhibition facilitates generation of polyfunctional stem cell memory-like CD8+ T cells for adoptive immunotherapy. OncoImmunology, 7(10). https://doi.org/10.1080/2162402X.2018.1488565

MLA:

Mousset, Charlotte M., et al. "Ex vivo AKT-inhibition facilitates generation of polyfunctional stem cell memory-like CD8+ T cells for adoptive immunotherapy." OncoImmunology 7.10 (2018).

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