Inhibiting Free Fatty Acid Transport to Improve CAR-T Cell Therapy of Relapsed B-Cell Acute Lymphoblastic Leukemia
Bibliographic record
Abstract
Introduction: B-cell acute lymphoblastic leukemia (B-ALL) resistant to conventional chemotherapy is a leading cause of cancer-related mortality in children and young adults. Although CD19-directed Chimeric Antigen Receptor T-cell (CAR-T) therapy shows promise for relapsed/refractory B-ALL, its effectiveness is often compromised by leukemia-intrinsic resistance mechanisms that remain unclear. Recent evidence suggests that TP53 mutations negatively affect the long-term efficacy of CD19 CAR-T therapy in B-ALL, despite initial trials not identifying high-risk genetic features impacting early clinical responses. TP53 loss-of-function mutations, although rare at diagnosis, are enriched in relapsed B-ALL and associated with chemotherapy resistance and poor survival. Methods and Results: To dissect the B-ALL-intrinsic role of p53 during CAR-T therapy, we found that TP53 loss-of-function mutations in a subset of human B-ALL cell lines conferred resistance to CAR-T cell killing in vitro and in vivo. To elucidate the pathways driving CAR-T resistance in TP53-mutated (mut) B-ALL cells, we performed genome-wide CRISPR/Cas9 screening on isogenic TP53-wildtype (wt) and TP53-mut CD19+ B-ALL cell lines treated with CD19-CAR-T cells ex vivo. This screening approach identified the free fatty acid transporter FATP2 (encoded by SLC27A2) as a critical factor; as its genetic ablation enhanced CAR-T efficacy against TP53-mut B-ALL lines. Analysis of RNA-seq data from 1104 pediatric B-ALL patients revealed that high SLC27A2 mRNA expression at B-ALL diagnosis correlated with poor overall survival and increased free fatty acid metabolism. To understand the mechanism of FATP2 activity in B-ALL survival, we found FATP2-expressing B-ALL lines internalize long-chain free fatty acids more efficiently than non-FATP2-expressing human B-ALL cell lines. Additionally, FATP2-mediated CAR-T resistance in TP53-mut B-ALL cells was reversible by depleting exogenous fatty acids. Stable isotope free fatty acid uptake tracing revealed a role for FATP2 in promoting succinate accumulation in TP53-mutated B-ALL cells, thus significantly altering cellular metabolism that may have contributed to CAR-T resistance. Ongoing experiments aim to identify the precise mechanisms contributing to leukemia-intrinsic, FATP2-dependent CAR-T resistance. Conclusions: Our studies suggest that FATP2 expression drives TP53-mutant B-ALL CAR-T resistance by facilitating the uptake of exogenous free fatty acids. Collectively, we propose targeting free fatty acid transport as a specific metabolic vulnerability in B-ALL that might improve CAR-T therapy outcomes.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".