scholarly journals Mastering an exhausting marathon: how CD8 + T cells fine‐tune metabolic fitness

2022 ◽  
Author(s):  
Anna M Schulz ◽  
Dietmar Zehn
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Metabolic Fitness ◽  
Fine Tune

scholarly journals 668 Lipid-instructed metabolic rewiring unleash the anti-tumor potential of CD8+ T cells

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A696-A696
Author(s):  
Teresa Manzo ◽  
Carina Nava Lauveson ◽  
Teresa Maria Frasconi ◽  
Silvia Tiberti ◽  
Ignazio Caruana ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
Cd8 T Cells ◽  
Mitochondrial Function ◽  
Cd8 T Cell ◽  
T Cell Differentiation ◽  
Metabolic Reprogramming ◽  
Tumor Control ◽  
Metabolic Fitness

BackgroundAdoptive cell therapy (ACT) harnesses the immune system to recognise tumor cells and carry out an anti-tumor function. However, metabolic constraints imposed by the tumour microenvironment (TME) suppress anti-tumor responses of CTL by reshaping their metabolism and epigenetic landscape. We have recently demonstrated that progressive accumulation of specific long-chain fatty acids (LCFAs) impair mitochondrial function and drives CD8+ T cell dysfunction. In this scenario, maintaining T cells in a less-differentiated state and with high metabolic plasticity during ex vivo T cell production and after infusion may have a strong therapeutic impact. Here, we propose a novel strategy to boost ACT efficacy by implementing T cell long-term functionality, metabolic fitness and preventing exhaustion through lipid-induced mitochondrial rewiring.MethodsWe screen different LCFAs and assess their ability to shape CD8+ T cell differentiation using multi-parametric flow cytometry, proliferation and cytotoxic assays, together with a complete transcriptomic and epigenomic profiling. Metabolic reprogramming of lipid-treated CD8+ T cell was examined by bioenergetic flux measurements paired with metabolomic and lipidomic analysis. Finally, the anti-tumor responses of lipid-instructed CD8 T cells was evaluated in a melanoma mouse model, known to poorly respond to immunotherapy.ResultsLCFAs-treated CD8+ T cells are endowed with highly effector and cytotoxic features but still retaining a memory-like phenotype with decreased PD1 protein levels. Consistently, analysis of the bioenergetic profile and mitochondrial activity has shown that LCFA-instructed CD8+ T cells display a greater mitochondrial fitness. Thus, in vitro LCFA-instructed CD8+ T cells are characterized by higher mitochondrial fitness, potent functionality, memory-like phenotype and PD-1 down-regulation, overall evoking the ideal T cell population associated with a productive anti-tumor response. The therapeutic potential of CD8 T cells lipid-induced metabolic rewiring was further confirmed in vivo. ACT performed with LCFA-reprogrammed CD8 T cells induces higher frequency of memory T cells, which show high polyfunctionality and mitochondrial function, decreased PD1 expression, ultimately resulting in improved tumor control. In addition, LCFA-induced metabolic rewiring during manufacturing of human CAR-redirected T cells, generated a CD8+ T cell memory-like population with higher mitochondrial fitness coupled with a much potent cytotoxic activity.ConclusionsThese results suggest that LCFAs dictate the fate of CD8+ T cell differentiation and could be considered as a molecular switch to fine-tune memory T cell formation and metabolic fitness maintenance, linking lipid metabolism to anti-tumor surveillance. This will be of fundamental importance for a new generation of adoptive T cell-based therapies.Ethics ApprovalThe experiments described were performed in accordance with the European Union Guideline on Animal Experiments and mouse protocols were approved by Italian Ministry of Health and the IEO Committee.

scholarly journals The purinergic receptor P2RX7 directs metabolic fitness of long-lived memory CD8+ T cells

Nature ◽  
2018 ◽  
Vol 559 (7713) ◽  
pp. 264-268 ◽  
Author(s):  
Henrique Borges da Silva ◽  
Lalit K. Beura ◽  
Haiguang Wang ◽  
Eric A. Hanse ◽  
Reshma Gore ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Purinergic Receptor ◽  
Memory Cd8 T Cells ◽  
Metabolic Fitness

scholarly journals CD73 Ectonucleotidase Restrains CD8+ T Cell Metabolic Fitness and Anti-tumoral Activity

2021 ◽  
Vol 9 ◽  
Author(s):  
Pedro Briceño ◽  
Elizabeth Rivas-Yañez ◽  
Mariana V. Rosemblatt ◽  
Brian Parra-Tello ◽  
Paula Farías ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cytotoxic T Cells ◽  
Cd8 T Cell ◽  
Tumor Burden ◽  
Effector Cells ◽  
Cd73 Expression ◽  
Metabolic Fitness

CD39 and CD73 are ectoenzymes that dephosphorylate ATP into its metabolites; ADP, AMP, and adenosine, and thus are considered instrumental in the development of immunosuppressive microenvironments. We have previously shown that within the CD8+ T cell population, naïve and memory cells express the CD73 ectonucleotidase, while terminally differentiated effector cells are devoid of this enzyme. This evidence suggests that adenosine might exert an autocrine effect on CD8+ T cells during T cell differentiation. To study the possible role of CD73 and adenosine during this process, we compared the expression of the adenosinergic signaling components, the phenotype, and the functional properties between CD73-deficient and WT CD8+ T cells. Upon activation, we observed an upregulation of CD73 expression in CD8+ T cells along with an upregulation of the adenosine A2A receptor. Interestingly, when we differentiated CD8+ T cells to Tc1 cells in vitro, we observed that these cells produce adenosine and that CD73-deficient cells present a higher cytotoxic potential evidenced by an increase in IFN-γ, TNF-α, and granzyme B production. Moreover, CD73-deficient cells presented a increased glucose uptake and higher mitochondrial respiration, indicating that this ectonucleotidase restrict the mitochondrial capacity in CD8+ T cells. In agreement, when adoptively transferred, antigen-specific CD73-deficient CD8+ T cells were more effective in reducing the tumor burden in B16.OVA melanoma-bearing mice and presented lower levels of exhaustion markers than wild type cells. All these data suggest an autocrine effect of CD73-mediated adenosine production, limiting differentiation and cytotoxic T cells’ metabolic fitness.

Abstract A19: PD-1 modulation promotes antitumor immunity by improving metabolic fitness of both PD-1+ and PD-1- CD8+ T cells in the tumor

2018 ◽  
Author(s):  
Kristen E. Pauken ◽  
Vikram R. Juneja ◽  
Peter T. Sage ◽  
Martin W. LaFleur ◽  
Juhi R. Kuchroo ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Antitumor Immunity ◽  
Metabolic Fitness

scholarly journals Metformin enhances anti-mycobacterial responses by educating immunometabolic circuits of CD8+ T cells

2020 ◽  
Author(s):  
Julia Böhme ◽  
Nuria Martinez ◽  
Shamin Li ◽  
Andrea Lee ◽  
Mardiana Marzuki ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Protective Efficacy ◽  
Acid Oxidation ◽  
Diabetic Patients ◽  
Mass Cytometry ◽  
Mitochondrial Mass ◽  
Survival Capacity ◽  
Metabolic Fitness

AbstractDiabetic patients taking metformin have lower risk for Mycobacterium tuberculosis (Mtb) infection, progression from infection to tuberculosis (TB) disease, TB morality and TB recurrence. However, a detailed mechanistic understanding of metformin’s protective immunological benefits on host resistance to TB is lacking. In this study, using mass cytometry we show that metformin treatment expands memory-like antigen-inexperienced CD8+CXCR3+ T cells in naïve mice, and in healthy and diabetic humans. Metformin-educated CD8+ T cells have increased (i) mitochondrial mass, oxidative phosphorylation, and fatty acid oxidation; (ii) survival capacity; and (iii) anti-mycobacterial properties. CD8+ T cells from CXCR3−/− mice did not exhibit metformin-mediated metabolic programming. In BCG-vaccinated mice and guinea pigs, metformin enhanced immunogenicity and protective efficacy against Mtb challenge. Collectively, our results demonstrate an important role of CD8+ T cells in metformin-derived host metabolic-fitness towards Mtb infection.

Impaired Metabolic Fitness in T Cells in Chronic Lymphocytic Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2528-2528
Author(s):  
Armando van Bruggen ◽  
Sanne Endstra ◽  
Gerritje J.W. van der Windt ◽  
Arnon P. Kater
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
Cd8 T Cells ◽  
Aerobic Glycolysis ◽  
Cell Metabolism ◽  
Cd8 T Cell ◽  
Lymphocytic Leukemia ◽  
Activation Markers ◽  
Metabolic Fitness

Abstract Quiescent T cells primarily use oxidative phosphorylation (OXPHOS) to generate ATP, while in response to activation T cells switch to high rates of aerobic glycolysis, also known as the Warburg effect. While less efficient in overall ATP production, this switch to aerobic glycolysis is essential to produce cellular biomass needed for proliferation, and is required for T cell effector functions. In chronic lymphocytic leukemia (CLL) acquired T cell dysregulation occurs independent of treatment with functional impairment and exhaustion of T cells. As tumor-imposed metabolic restrictions in mouse models can mediate T cell hyporesponsiveness during cancer, we hypothesized that in the context of CLL T cell metabolism might be altered. Comparison of gene expression profiles of T cells from patients with CLL and age-matched healthy donors (HD) revealed a highly significant increase in the expression of genes in the OXPHOS pathway (P=3.4*10-15) in the CD8 T cell compartment. In corroboration with these array results, we found that in naïve CD8 T cells in CLL, mitochondrial mass and respiration were significantly increased. In addition, increased mitochondrial ROS production was observed in the naïve CD8 T cell subset. Using Seahorse EFA technology on sorted CD8 T cells from CLL and age-matched HD, we found increased oxygen consumption rates in CLL derived CD8 T cells, indicating increased OXPHOS, while the spare respiratory capacity was lower in these cells, indicating impeded ability to cope with cellular stress. Extracellular acidification rates (ECAR; indicating glycolysis), and uptake of fluorescently labeled glucose were similar in CD8 T cells from CLL patients and HD. Next, we studied the metabolic plasticity of CLL derived T cells by stimulation of PBMCs from CLL patients and age-matched HD using anti-CD3/CD28 antibodies. Two days after stimulation, CLL derived T cells had diminished expression of activation markers CD25 and CD38, which correlated with reduced uptake of fluorescently labeled glucose. Moreover, preliminary Seahorse analysis of the immediate response to stimulation with anti-CD3/CD28 showed a reduced increase in ECAR in CLL derived CD8 T cells, indicating an impairment of the glycolytic switch in these cells. Taken together, these results demonstrate that the metabolic fitness of CD8 T cells is impaired in CLL at resting state and after activation. Boosting T cell metabolism in CLL might therefore improve existing immunotherapies in CLL such as CAR-T cell therapy. This work is funded by VENI and VIDI grants from the Dutch Organisation for Scientific Research, and a Marie Curie Career Integration Grant from the European Union. Disclosures Kater: Celgene: Research Funding.

Author response for "4‐1BB costimulation promotes bystander activation of human CD8 T cells"

2020 ◽  
Author(s):  
Manuel Reithofer ◽  
Sandra Rosskopf ◽  
Judith Leitner ◽  
Claire Battin ◽  
Barbara Bohle ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Author Response ◽  
Bystander Activation
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