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Inhibiting lysine demethylase 1A improves L1CAM-specific CAR T cell therapy by unleashing antigen-independent killing via the FAS-FASL axis

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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. and Grunewald, L. and Andersch, L. and Schwiebert, S. and Klaus, A. and Winkler, A. and Astrahantseff, K. and Eggert, A. and Henssen, A.G. and Schulte, J.H. and 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
Page Range:5489
Date:31 October 2021
Official Publication:https://doi.org/10.3390/cancers13215489
PubMed:View item in PubMed

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