Abstract B012: Reviving exhausted T cells in pediatric B-cell acute lymphoblastic leukemia
Notice bibliographique
Résumé
Abstract Despite significant treatment advances, the poor long-term prognosis for children with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) persists. The application of immune cell-based therapies, such as chimeric antigen receptor-expressing T cells and bispecific T-cell engagers, has improved progression-free survival for many B-ALL patients. However, many of these patients still experience disease relapse. While tumours are widely recognized to influence T cell function, this relationship has not been extensively studied in B-ALL. A clinically silent pre-leukemic phase usually precedes childhood B-ALL. Since only a small percentage of children subsequently develop disease, the impact of pre-leukemia on T cell function remains elusive. To address this knowledge gap, we investigated the development of T cell dysfunction in B-ALL and explored ways to restore it using in situ and transplanted leukemia models Using the Emu-Ret transgenic mouse model of hyperdiploid B-ALL, we investigated the induction of exhaustion-associated marker expression (PD-1, CTLA-4 and Tim-3) on T cells. Longitudinal analysis of marker expression revealed that an upregulation of multiple immune checkpoints such as PD-1 and Tim-3, on T cells occurred only in the presence of leukemia cells, not during the extended preleukemia phase. This suggests that T cell exhaustion occurs exclusively during the established malignancy phase, highlighting the evolving nature of T cell responses as disease progresses. Next, we measured exhaustion-associated marker expression in a syngeneic model of transplanted B-ALL. While expression of PD-1 and Tim-3 on T cells correlated with disease progression, a significant increase in these markers was already detectable at low leukemia burden. This indicates that T cell exhaustion is not merely a reflection of high disease burden and highlights the differing impact exerted by preleukemic and leukemic cells on T cells. Phenotypically exhausted T cells from both mouse models showed reduced proliferation, activation, and cytokine secretion. Previously, we have demonstrated the ability of toll-like receptor (TLR) ligands to induce immune control over B-ALL cells. Thus, we investigated the impact of CpG oligodeoxynucleotides (CpG ODN), a ligand for TLR-9, to overcome T cell dysfunction. The treatment of leukemia bearing mice with CpG ODN led to a decrease in PD-1 and Tim-3 expression on T cells, which was also associated with a reduction in leukemia burden. Lastly, the administration of a checkpoint blockade antibodies, with or without TLR agonists as adjuvant therapy led to increased survival of leukemia bearing mice. Overall, this study demonstrates the functional impact of interactions between B-ALL cells and the immune system. The findings from this study may inform therapeutic approaches to overcome B-ALL immune evasion mechanisms and enhance patient outcomes. Citation Format: Tanmaya Atre, Gregor S.D Reid. Reviving exhausted T cells in pediatric B-cell acute lymphoblastic leukemia [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr B012.
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 machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 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) | 0,001 | 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 source (Gemma direct ou Codex distillé), 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 ».