Abstract B052: Peroxisome proliferator-activated receptor delta agonist GW501516 enhances the efficacy of adoptive cell therapy
Bibliographic record
Abstract
Abstract Adoptive cell therapy (ACT) has demonstrated tremendous promise for the treatment of metastatic melanoma. Emerging evidence has indicated that memory CD8+ T cells (Tcm) are superior mediators of ACT than are effector CD8+ T cells (Teff) due to a superior ability to persist in vivo. Underpinning the survival advantage of Tcm is a shift in cellular metabolism away from aerobic glycolysis to instead favor fatty acid oxidation (FAO). This switch to FAO in Tcm requires the expression of carnitine palmitoyl transferase 1a (CPT1a), the rate-limiting enzyme of FAO. Here, we investigated the impact of the peroxisome proliferator-activated receptor (PPAR)δ/β agonist GW501516 (GW), an agent known to boost CPT1a expression and promote FAO in other tissues, on CD8+ T cell metabolism, function and performance in the murine B16-GP33 melanoma model. Via the activation of both PPARα and PPARδ/β we found that GW treatment increased CPT1a expression in activated CD8+ T cells. Using a metabolomics approach, we demonstrated that GW treatment increased the abundance of multiple different acylcarnitines, consistent with enhanced FAO. Unexpectedly, we also found that T cells activated in the presence of GW as well as inflammatory signals, either LPS-matured dendritic cells (DCs) or IL-12, demonstrated enhanced production of interferon-γ. This increase in interferon-γ correlated with increased expression of the transcription factor T-bet. Despite the high T-bet expression, a characteristic of short-lived effector cells, GW-treated CD8+ T cells activated by LPS-treated DCs demonstrated an enhanced ability to persist in vivo. They also demonstrated improved performance in our murine model of ACT. Thus, our data indicates that combined treatment of CD8+ T cells with GW and inflammatory signals can result in in Teff cell with improved ability to produce cytokines but that have also shifted their metabolism to increase FAO akin to Tcm, allowing for enhanced in vivo persistence. These data identify GW501516, and potentially other combined PPARα and PPARδ/β agonists currently being developed, as attractive candidates for further studies and rapid translation into clinical trials of ACT. Citation Format: Samuel Saibil, Michael St. Paul, Pamela Ohahsi. Peroxisome proliferator-activated receptor delta agonist GW501516 enhances the efficacy of adoptive cell therapy [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B052.
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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) | 0.001 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
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".