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| Item Type: | Article |
|---|---|
| Title: | Inhibiting lysine demethylase 1A improves L1CAM-specific CAR T cell therapy by unleashing antigen-independent killing via the FAS-FASL axis |
| Creators Name: | Sulejmani, O., Grunewald, L., Andersch, L., Schwiebert, S., Klaus, A., Winkler, A., Astrahantseff, K., Eggert, A., Henssen, A.G., Schulte, J.H., Anders, K. and Künkele, A. |
| Abstract: | Chimeric antigen receptor (CAR) T cell therapy has emerged as a promising treatment strategy, however, therapeutic success against solid tumors such as neuroblastoma remains modest. Recurrence of antigen-poor tumor variants often ultimately results in treatment failure. Using antigen-independent killing mechanisms such as the FAS receptor (FAS)-FAS ligand (FASL) axis through epigenetic manipulation may be a way to counteract the escape achieved by antigen downregulation. Analysis of public RNA-sequencing data from primary neuroblastomas revealed that a particular epigenetic modifier, the histone lysine demethylase 1A (KDM1A), correlated negatively with FAS expression. KDM1A is known to interact with TP53 to repress TP53-mediated transcriptional activation of genes, including FAS. We showed that pharmacologically blocking KDM1A activity in neuroblastoma cells with the small molecule inhibitor, SP-2509, increased FAS cell-surface expression in a strictly TP53-dependent manner. FAS upregulation sensitized neuroblastoma cells to FAS-FASL-dependent killing and augmented L1CAM-directed CAR T cell therapy against antigen-poor or even antigen-negative tumor cells in vitro. The improved therapeutic response was abrogated when the FAS-FASL interaction was abolished with an antagonistic FAS antibody. Our results show that KDM1A inhibition unleashes an antigen-independent killing mechanism via the FAS-FASL axis to make tumor cell variants that partially or totally suppress antigen expression susceptible to CAR T cell therapy. |
| Keywords: | Neuroblastoma, Pediatric Cancer, Adoptive Immunotherapy, Epigenetic Regulation, Solid Tumors, Antigen-Independent Tumor Cytotoxicity |
| Source: | Cancers |
| ISSN: | 2072-6694 |
| Publisher: | MDPI |
| Volume: | 13 |
| Number: | 21 |
| Page Range: | 5489 |
| Date: | 31 October 2021 |
| Official Publication: | https://doi.org/10.3390/cancers13215489 |
| PubMed: | View item in PubMed |
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