Abstract A078 Targeted ferroptosis induction enhances chemotherapy and natural killer cell immunotherapy in neuroblastoma
Notice bibliographique
Résumé
Abstract Background Neuroblastoma (NB) is a heterogeneous pediatric solid tumor of the sympathetic nervous system that accounts for 15% of pediatric childhood deaths. High-risk NB is often chemoresistant, with <50% survival. Additionally, its low mutational load and immunosuppressive tumor microenvironment (i-TME) have hindered the success of immunotherapy. NB has a strong dependency on iron metabolism, making induction of ferroptosis, an iron-mediated immunogenic cell death, a potential treatment for chemoresistant NB. Ferroptosis also has the potential to enhace immune cell therapy. Natural killer (NK) cells have emerged as a promising immunotherapeutic tool for pediatric tumors, as they don’t depend on specific mutations, but new strategies are needed to overcome the i-TME. Comnination with immunogenic ferroptosis induction could be a solution. Here we explore the combination of ferroptosis induction, standard-of-care chemotherapy and NK cell therapy, to identify novel therapeutic combinations to tackle high-risk NB. Results Using NB patient-derived models, we analyzed multiple ferroptosis-inducing compounds with different mechanisms of action. Auranofin (thioredoxin reductase inhibitor) and RSL3 (inhibitor of glutathione peroxidase 4, GPX4) were identified as promising agents against chemoresistant NB. Both agents increased survival, reduced tumor growth, and decreased the population of chemoresistant immature mesenchymal-like cells in vivo. Upon combination with chemotherapy, the distinct mechanisms of ferroptosis induction led to differential interactions with COJEC, the standard-of-care 5-drug cocktail used to treat NB patients. Auranofin exhibited an additive effect, while RSL3 showed an antagonistic interaction due to upregulation of GPX4 and other ferroptosis inhibitors by COJEC, primarily driven by etoposide. The combination Auranofin-COJEC decreased tumor growth and increased survival in a chemoresistant NB patient-derived xenograft (PDX) model through ferritinophagy, lysosome accumulation, and iron overload. Upon RNA analysis of PDX tumors treated with Auranofin and RSL3, we observed that RSL3 enhanced the expression of pathways associated with inflammation, while Auranofin had the opposite effect. Treatment with ferroptosis-inducing agents in vitro led to the release of damage-associated molecular patterns (DAMPs) and, when combined in a sequential manner with NK cell therapy, an additive effect was observed. Conclusions The use of ferroptosis-inducing agents, based on their mechanisms of action, in combination with chemotherapy and immunotherapy, is a feasible and promising strategy that outperforms standard-of-care chemotherapy in chemoresistant NB. Future work should identify which ferroptosis-inducing mechanisms are best to combine with chemotherapy and immunotherapy, and which patients can benefit from each combination based on tumor characteristics. The availability of multiple ferrotosis-inducing mechanism opens the door to personalized treatment protocols. Citation Format: Adriana Mañas, Alexandra Seger, Aleksandra Adamska, Kyriaki Smyrilli, Lucía Sánchez, Antonio Pérez-Martínez, Daniel Bexell. Targeted ferroptosis induction enhances chemotherapy and natural killer cell immunotherapy in neuroblastoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A078.
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 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 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 ».