Abstract:Stem cells are defined by the ability to self-renew and to generate differentiated progeny, qualities that are maintained by evolutionarily conserved pathways that can lead to cancer when deregulated. There is now evidence that these stem cell-like attributes and signalling pathways are also shared among subsets of mature memory T lymphocytes. We discuss how using stem cell-like T cells can overcome the limitations of current adoptive T cell therapies, including inefficient T cell engraftment, persistence and … Show more
“…Improved clinical efficacy of adoptive T cell therapy could be reached by generating tumor-specific T cell products with an early differentiation state, as they show superior longevity and proliferative capacity. 1-3,5-9,15-21,24,25,29-35 This could be accomplished by inhibition of the AKT pathway, as was previously shown by us and others. 15-21 In this study, we aimed to further optimize AKT-inhibited CD8 + T cells by exploring AKT-inhibitors with diverse modality of action, and further characterize these cells for their phenotype, transcriptome, metabolism and functionality.…”
Section: Discussionmentioning
confidence: 60%
“…Further analysis of AktiVIII- and GDC-treated T cells showed enrichment of hematopoietic stem cell associated genes (Figure 3D), emphasizing the existence of a conserved molecular network regulating self-renewal and differentiation in stem cells and early memory T lymphocytes. 25 Interestingly, AKT-inhibited T cells were also enriched with hypoxia pathway genes and Hif1α targets compared to control cells (Figure 3D). Together, the transcriptome analysis demonstrates unique profiles for all AKT-inhibited T cell products, which exhibit close resemblance with T SCM cells and enrichment of specific pathways and effector characteristics, independent of the mode of inhibition.10.1080/2162402X.2018.1488565-F0003Figure 3.AKT-inhibited CD8 + T cells cluster with T SCM cells and are enriched for hypoxia related- and Hif1α target genes.…”
Section: Resultsmentioning
confidence: 96%
“…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.…”
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.
“…Improved clinical efficacy of adoptive T cell therapy could be reached by generating tumor-specific T cell products with an early differentiation state, as they show superior longevity and proliferative capacity. 1-3,5-9,15-21,24,25,29-35 This could be accomplished by inhibition of the AKT pathway, as was previously shown by us and others. 15-21 In this study, we aimed to further optimize AKT-inhibited CD8 + T cells by exploring AKT-inhibitors with diverse modality of action, and further characterize these cells for their phenotype, transcriptome, metabolism and functionality.…”
Section: Discussionmentioning
confidence: 60%
“…Further analysis of AktiVIII- and GDC-treated T cells showed enrichment of hematopoietic stem cell associated genes (Figure 3D), emphasizing the existence of a conserved molecular network regulating self-renewal and differentiation in stem cells and early memory T lymphocytes. 25 Interestingly, AKT-inhibited T cells were also enriched with hypoxia pathway genes and Hif1α targets compared to control cells (Figure 3D). Together, the transcriptome analysis demonstrates unique profiles for all AKT-inhibited T cell products, which exhibit close resemblance with T SCM cells and enrichment of specific pathways and effector characteristics, independent of the mode of inhibition.10.1080/2162402X.2018.1488565-F0003Figure 3.AKT-inhibited CD8 + T cells cluster with T SCM cells and are enriched for hypoxia related- and Hif1α target genes.…”
Section: Resultsmentioning
confidence: 96%
“…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.…”
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.
“…T cells, a subpopulation of adaptive lymphocytes, play an important role in immunity to intracellular pathogens and tumors (Gattinoni et al 2012;Klenerman and Hill 2005;Kuang et al 2010;Lu et al 2014). They also contribute to the regulation of pathologic processes such as autoimmune and allergic disorders (Huber et al 2009;Kim and Cantor 2011;Loser et al 2010;Tang et al 2012;Visekruna et al 2013).…”
It is well established that CD8? T cells constitute an important branch of adaptive immunity contributing to clearance of intracellular pathogens and providing long-term protection. These functions are mostly fulfilled by the best characterized subpopulation of CD8? T cells, the cytotoxic T lymphocytes (also called Tc1 cells), owing to their ability to kill infected cells and to secrete cytokines such as interferon-c and tumor necrosis factor-a. However, there is growing evidence for alternative CD8?
“…Human serum was removed to minimize risk of viral contamination, process steps were moved from open-to closed-system operations to minimize the risk of microbial contamination, and additional steps were standardized to maximize process consistency. Furthermore, an extended ex vivo expansion of T cells was felt to be potentially detrimental by driving them into exhaustion [27] and thus, a shorter engineered manufacturing process was desirable [28]. The optimized axicabtagene ciloleucel manufacturing method is now able to produce CAR T cells on a large scale in a rapid 6-8 d functionally closed process.…”
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