234 Bead-bound antibody-activation of T cells provides sub-optimal metabolic programming and tumour control compared to dendritic cell-activated T cells
Notice bibliographique
Résumé
<h3>Background</h3> Adoptive cell therapies (ACT), including chimeric antigen receptor (CAR) or T cell receptor (TCR) transgenic T cells, have demonstrated impressive efficacy for the treatment of cancer. Unfortunately, ACT still does not result in durable responses for many patients.<sup>1</sup> Much investigation has centered around defining the characteristics of T cells that drive the clinical efficacy of ACT. Metabolic programming, and particularly oxidative metabolism, has emerged as a hallmark of T cells associated with superior performance in ACT due to important associations with <i>in vivo</i> persistence and metabolic resiliency in nutrient limiting environments.<sup>2–7</sup> However, further investigation is required to define the optimal <i>ex vivo</i> activation conditions to impart optimal metabolic programming on the T cells used for ACT. We therefore interrogated the difference in metabolic programming resulting from activation with antibody-coated beads versus peptide-pulsed dendritic cells (DCs). <h3>Methods</h3> CD8+ T cells were isolated from P14 TCR transgenic mice (recognizing H2-D<sup>b</sup> gp33 peptide from lymphocytic choriomeningitis virus). T cells were activated with either bone-marrow derived DCs pulsed with gp33 peptide (1:10 DC:T cells) or with bead-bound anti-CD3/anti-CD28 antibodies (1:1 beads:T cells). Oxidative and glycolytic metabolism were measured by Seahorse Extracellular Flux analyzer. These data were used to calculate ATP production rate. <i>In vivo</i>, we examined the performance of these differentially activated P14 T cells to control the growth of subcutaneously implanted B16-gp33 melanoma tumours. <h3>Results</h3> DC-activated T cells showed increased oxidative and glycolytic metabolism compared to bead-bound antibody-activated T cells. This resulted in an enhanced rate of ATP production in the DC-activated T cells. These metabolic data were associated with efficacy in the B16-gp33 model of ACT. Mice treated with DC-activated T cells had significantly diminished tumour growth and improved survival when compared to the bead-bound antibody-activation treatment condition. The latter treatment provided little advantage over the control (no treatment) group. <h3>Conclusions</h3> Bead-bound antibody activation of T cells at a ratio of 1:1 (beads:T cells) provides sub-optimal metabolic priming which is associated with decreased performance in ACT, particularly when compared to DC-activated T cells. Further investigation into the metabolic programming of T cells by different activation conditions may reveal metabolic or signaling modules that can be modified in these conditions to improve therapy. This is relevant to the efficacy of CAR T cell therapy which often uses bead-activation of T cells for clinical protocols. <h3>References</h3> C. H. June, R. S. O’Connor, O. U. Kawalekar, S. Ghassemi, and M. C. Milone, “CAR T cell immunotherapy for human cancer,” <i>Science</i>, vol. <b>359</b>, no. 6382, pp. 1361–1365, Mar. 2018; doi: 10.1126/science.aar6711. S. D. Saibil <i>et al</i>., “Activation of Peroxisome Proliferator-Activated Receptors a and d Synergizes with Inflammatory Signals to Enhance Adoptive Cell Therapy,” <i>Cancer Res</i>, vol. <b>79</b>, no. 3, pp. 445–451, Feb. 2019; doi: 10.1158/0008-5472.CAN-17-3053. M. St Paul <i>et al</i>., “Coenzyme A fuels T cell anti-tumor immunity,” <i>Cell Metab</i>, vol. <b>33</b>, no. 12, pp. 2415-2427.e6, Dec. 2021; doi: 10.1016/j.cmet.2021.11.010. G. J. W. van der Windt <i>et al</i>., “Mitochondrial Respiratory Capacity Is a Critical Regulator of CD8+ T Cell Memory Development,” <i>Immunity</i>, vol. <b>36</b>, no. 1, pp. 68–78, Jan. 2012; doi: 10.1016/j.immuni.2011.12.007. Y. Zhang <i>et al</i>., “Enhancing CD8+ T Cell Fatty Acid Catabolism within a Metabolically Challenging Tumor Microenvironment Increases the Efficacy of Melanoma Immunotherapy,” <i>Cancer Cell</i>, vol. <b>32</b>, no. 3, pp. 377-391.e9, Sep. 2017; doi: 10.1016/j.ccell.2017.08.004. Y. Sun <i>et al</i>., “Zbtb20 Restrains CD8 T Cell Immunometabolism and Restricts Memory Differentiation and Antitumor Immunity,” <i>The Journal of Immunology</i>, vol. <b>205</b>, no. 10, pp. 2649–2666, Nov. 2020; doi: 10.4049/jimmunol.2000459. M. D. Buck <i>et al</i>., “Mitochondrial Dynamics Controls T Cell Fate through Metabolic Programming,” <i>Cell</i>, vol. <b>166</b>, no. 1, pp. 63–76, Jun. 2016; doi: 10.1016/j.cell.2016.05.035. <h3>Ethics Approval</h3> This study was approved by The University Health Network Animal Care Committee; approval number 929.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».