Akt1 and -2 inhibition diminishes terminal differentiation and enhances central memory CD8<sup>+</sup>T-cell proliferation and survival

Eid, Rasha Abu; Friedman, Kevin M.; Mkrtichyan, Mikayel; Walens, Andrea; King, William C.; Janik, John E.; Khleif, Samir N.

doi:10.1080/2162402x.2015.1005448

Cited by 39 publications

(30 citation statements)

References 25 publications

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“…Here, we observed upregulated naïve- and memory-associated genes, while expression of effector-associated genes was lower compared to control T cells. These data are in agreement with previously published data on AKT-inhibited T cells by us and others, 15-19 and confirms the extensive down-stream analysis by Klebanoff et al ., which highlights FOXO1 as the key player in this process. 18 With the increased expression of FOXO1 targets, increased expression of naïve-associated markers, and decreased expression of effector and apoptosis molecules, our AKT-inhibited cells possess unique and superior characteristics for adoptive cell therapy in cancer patients.…”

Section: Discussionsupporting

confidence: 94%

“…1-3,5-9,25,29,32,34 This perspective should promote further research and clinical translation of adoptive T cell therapy with interference of the PI3K/AKT/mTOR or Wnt-signalling pathway. 15-19,21,33 Here we show that AKT-inhibition can be used for the generation of a unique T SCM -like CD8 + T cell product for adoptive transfer. Though this is irrespective of the mode of action of the inhibitor, the choice of inhibitor does influence the characteristics and, thereby, possibly the clinical potency of the therapeutic product.…”

Section: Discussionmentioning

confidence: 79%

“…who reported that mouse T cells treated with AKT-inhibitor MK produced higher levels of IL-2. 19 Normally, terminally differentiated CD8 + T cells show diminished secretion of IL-2. 47 As our Akt-inhibited T cell products effeciently co-produced IL-2 and IFN-γ, this reflects the superior polyfunctionality of our T cells.…”

Section: Discussionmentioning

confidence: 99%

“…14 Therefore, we and others exploited pharmacological AKT-inhibition to generate early memory T SCM/CM -like CD8 + T cells for ex vivo adoptive cell therapy. 15-19 Previously, we demonstrated that minor histocompatability antigen (MiHA)-specific CD8 + T cells with early memory traits can be efficiently expanded ex vivo from the naïve repertoire in the presence of the allosteric Akt-inhibitor VIII (AktiVIII). 15 Importantly, these AKT-inhibited MiHA-specific CD8 + T cells displayed improved proliferation capacity upon antigen re-encounter after withdrawal of the AKT-inhibitor.…”

Section: Introductionmentioning

confidence: 99%

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

Mousset

Hobo

et al. 2018

OncoImmunology

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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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Section: Discussionsupporting

confidence: 94%

Section: Discussionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Mousset

Hobo

et al. 2018

OncoImmunology

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“…By contrast, unstimulated CAR T cells or T cells cocultured with CD19tumor cells produced minimal to no IFNγ and did not mediate tumor lysis, regardless of initial culture conditions. Activated T cells lose expression of CD62L, a lymphoid homing molecule and key marker of highly potent T cell subsets for adoptive immunotherapy (5,15,44), in an AKT1/2-dependent manner (45). We therefore evaluated whether inhibition of AKT could preserve expression of CD62L on CAR-engineered T cells.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of AKT signaling uncouples T cell differentiation from expansion for receptor-engineered adoptive immunotherapy

et al. 2017

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Hyaluronan‐binding by CD44 reduces the memory potential of activated murine CD8 T cells

et al. 2018

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Expansion and death of effector CD8 T cells are regulated to limit immunopathology and cells that escape contraction go on to generate immunological memory. CD44, a receptor for the extracellular matrix component hyaluronan, is a marker of activated and memory T cells. Here, we show with a murine model that the increase in CD44 expression and hyaluronan binding induced upon CD8 T cell activation was proportional to the strength of TCR engagement, thereby identifying the most strongly activated T cells. When CD44 and CD44 OT-I CD8 T cells were adoptively transferred into mice challenged with Listeria-OVA, there was a slight increase in the percentage of CD44 cells at the effector site. However, CD44 cells were out-competed by CD44 cells after the contraction phase in the lymphoid tissues, and the CD44 cells preferentially formed more memory cells. The hyaluronan-binding CD44 CD8 effector T cells showed increased pAkt expression, higher glucose uptake, and were more susceptible to cell death during the contraction phase compared to non-binding CD44 and CD44 OT-I CD8 T cells, suggesting that CD44 and its engagement with hyaluronan skews CD8 T cells toward a terminal effector differentiation state that reduces their ability to form memory cells.

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Akt1 and -2 inhibition diminishes terminal differentiation and enhances central memory CD8⁺T-cell proliferation and survival

Cited by 39 publications

References 25 publications

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

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

Inhibition of AKT signaling uncouples T cell differentiation from expansion for receptor-engineered adoptive immunotherapy

Hyaluronan‐binding by CD44 reduces the memory potential of activated murine CD8 T cells

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Akt1 and -2 inhibition diminishes terminal differentiation and enhances central memory CD8+T-cell proliferation and survival

Cited by 39 publications

References 25 publications

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

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

Inhibition of AKT signaling uncouples T cell differentiation from expansion for receptor-engineered adoptive immunotherapy

Hyaluronan‐binding by CD44 reduces the memory potential of activated murine CD8 T cells

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Akt1 and -2 inhibition diminishes terminal differentiation and enhances central memory CD8⁺T-cell proliferation and survival

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

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