Lipid uptake via FATP2 enhances CAR-t therapy resistance in B-cell acute lymphoblastic leukemia
Notice bibliographique
Résumé
Abstract Chimeric Antigen Receptor T cell (CAR-T) therapy is highly effective for treating relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). Critically, for those patients who initially respond to CAR-T therapy (~80–90%), approximately 50% will relapse within one year of T cell infusion (Laetsch et al., 2023; Maude et al., 2014; Pasquini et al., 2020). Short duration of CAR-T cell persistence and loss of CAR target antigen expression represent major relapse mechanisms (Shah & Fry, 2019). Notably, the current CAR-T paradigm suggests that despite prior selection for chemo-resistant leukemia cells in relapsed/refractory patients, CAR-T cells overcome chemotherapy resistance by killing antigen-positive leukemia cells via perforin and granzyme and do not rely on the genotoxic or metabolic insults elicited by chemotherapy. However, emerging clinical evidence suggests that additional leukemia-intrinsic factors contributing to chemotherapy resistance may be linked to suboptimal CAR-T responses. Although TP53 mutations are uncommon at the time of pediatric B-ALL diagnosis—except in low-hypodiploid cases (Holmfeldt et al., 2013)—they are frequently acquired in relapsed or chemotherapy-refractory B-ALL (Hof et al., 2011) and have been linked to resistance to CD19-directed CAR-T therapy (Aldoss et al., 2025; Pan et al., 2020; Zhang et al., 2020). Therefore, there is an urgent need to understand how leukemia-intrinsic resistance mechanisms, such as TP53 mutations, contribute to CAR-T resistance. To test the impact of p53 activity in leukemia cell on CAR-T cell effectiveness, we generated multiple isogenic human CD19⁺ B-ALL cell lines harboring TP53 wild-type, a TP53 “hotspot” point mutation (p.G245D DNA-binding domain mutant), or TP53 frameshift mutations. Consistent with recent studies (Cox et al., 2025), we found TP53 mutations (point or frameshift) promote CAR-T resistance in human pre-B-ALL cell lines. Through genome-wide CRISPR/Cas9 screening of CAR-sensitive TP53 wildtype and CAR-resistant TP53-mutant CD19⁺ B-ALL cell lines, we identified Fatty Acid Transport Protein 2 (FATP2, encoded by SLC27A2) as a leukemia-intrinsic mechanism of CAR-T resistance in TP53-mutant B-ALL. FATP2, a transmembrane protein, regulates lipid homeostasis by facilitating long-chain fatty acid (LCFA) transport and exhibits very long-chain acyl-CoA synthetase activity, modulating the metabolism of very long-chain fatty acids (Black et al., 2016). We found that CAR-T resistance in both FATP2-expressing TP53-mutant B-ALL cell lines and patient-derived TP53-mutant B-ALL xenografts is dependent on exogenous lipid uptake in vitro and in vivo. Using 13C-labeled LCFA tracing, we found that CAR-resistant FATP2-expressing TP53-mutant B-ALL cell lines exhibited increased levels of LCFAs, and fatty acid-derived acyl-carnitine intermediates compared to isogenic CAR-sensitive B-ALL cells (TP53 wildtype B-ALL or FATP2-deficient TP53-mutant B-ALL), consistent with elevated fatty acid oxidation (FAO). To assess whether lipid mobilization and mitochondrial import contribute to CAR resistance, we treated isogenic B-ALL cells with the lipase inhibitor Lalistat-1 (LAL1i) or the CPT1 inhibitor Etomoxir—blocking fatty acid liberation from lipid droplets or mitochondrial transport of FAO substrates, respectively—during Mock or CAR-T co-culture. In TP53 wild-type B-ALL, CAR-T treatment responses were unaffected by the addition of LAL1i or Etomoxir. In contrast, TP53-mutant B-ALL exhibited significantly enhanced CAR-T sensitivity in the presence of either inhibitor, suggesting that FAO supports resistance in TP53-mutant B-ALL. These findings suggest a potential interaction between TP53 mutation status and fatty acid metabolism in mediating CAR-T resistance, although the precise regulatory relationship between p53 and SLC27A2/FATP2 remains unclear. Overall, our findings highlight a previously unappreciated link between lipid metabolism and CAR-T resistance in B-ALL. Future studies aim to understand the role of LCFA uptake in conventional chemotherapy responses, as well as determine whether pharmacological modulation of lipid uptake could enhance CAR-T efficacy, particularly in TP53-mutant disease.
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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 | 0,001 | 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) | 0,003 | 0,001 |
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 ».