Inhibiting Lysine Demethylase 1A Improves L1CAM-Specific CAR T Cell Therapy by Unleashing Antigen-Independent Killing via the FAS-FASL Axis

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 kil...

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Autores principales:	Ornela Sulejmani, Laura Grunewald, Lena Andersch, Silke Schwiebert, Anika Klaus, Annika Winkler, Kathy Astrahantseff, Angelika Eggert, Anton G. Henssen, Johannes H. Schulte, Kathleen Anders, Annette Künkele
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	neuroblastoma pediatric cancer adoptive immunotherapy epigenetic regulation solid tumors antigen-independent tumor cytotoxicity Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/075e1c199853426e8b3862f618c348e2
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spelling	oai:doaj.org-article:075e1c199853426e8b3862f618c348e22021-11-11T15:33:42ZInhibiting Lysine Demethylase 1A Improves L1CAM-Specific CAR T Cell Therapy by Unleashing Antigen-Independent Killing via the FAS-FASL Axis10.3390/cancers132154892072-6694https://doaj.org/article/075e1c199853426e8b3862f618c348e22021-10-01T00:00:00Zhttps://www.mdpi.com/2072-6694/13/21/5489https://doaj.org/toc/2072-6694Chimeric 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 <i>FAS</i>. 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.Ornela SulejmaniLaura GrunewaldLena AnderschSilke SchwiebertAnika KlausAnnika WinklerKathy AstrahantseffAngelika EggertAnton G. HenssenJohannes H. SchulteKathleen AndersAnnette KünkeleMDPI AGarticleneuroblastomapediatric canceradoptive immunotherapyepigenetic regulationsolid tumorsantigen-independent tumor cytotoxicityNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENCancers, Vol 13, Iss 5489, p 5489 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	neuroblastoma pediatric cancer adoptive immunotherapy epigenetic regulation solid tumors antigen-independent tumor cytotoxicity Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	neuroblastoma pediatric cancer adoptive immunotherapy epigenetic regulation solid tumors antigen-independent tumor cytotoxicity Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Ornela Sulejmani Laura Grunewald Lena Andersch Silke Schwiebert Anika Klaus Annika Winkler Kathy Astrahantseff Angelika Eggert Anton G. Henssen Johannes H. Schulte Kathleen Anders Annette Künkele Inhibiting Lysine Demethylase 1A Improves L1CAM-Specific CAR T Cell Therapy by Unleashing Antigen-Independent Killing via the FAS-FASL Axis
description	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 <i>FAS</i>. 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.
format	article
author	Ornela Sulejmani Laura Grunewald Lena Andersch Silke Schwiebert Anika Klaus Annika Winkler Kathy Astrahantseff Angelika Eggert Anton G. Henssen Johannes H. Schulte Kathleen Anders Annette Künkele
author_facet	Ornela Sulejmani Laura Grunewald Lena Andersch Silke Schwiebert Anika Klaus Annika Winkler Kathy Astrahantseff Angelika Eggert Anton G. Henssen Johannes H. Schulte Kathleen Anders Annette Künkele
author_sort	Ornela Sulejmani
title	Inhibiting Lysine Demethylase 1A Improves L1CAM-Specific CAR T Cell Therapy by Unleashing Antigen-Independent Killing via the FAS-FASL Axis
title_short	Inhibiting Lysine Demethylase 1A Improves L1CAM-Specific CAR T Cell Therapy by Unleashing Antigen-Independent Killing via the FAS-FASL Axis
title_full	Inhibiting Lysine Demethylase 1A Improves L1CAM-Specific CAR T Cell Therapy by Unleashing Antigen-Independent Killing via the FAS-FASL Axis
title_fullStr	Inhibiting Lysine Demethylase 1A Improves L1CAM-Specific CAR T Cell Therapy by Unleashing Antigen-Independent Killing via the FAS-FASL Axis
title_full_unstemmed	Inhibiting Lysine Demethylase 1A Improves L1CAM-Specific CAR T Cell Therapy by Unleashing Antigen-Independent Killing via the FAS-FASL Axis
title_sort	inhibiting lysine demethylase 1a improves l1cam-specific car t cell therapy by unleashing antigen-independent killing via the fas-fasl axis
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/075e1c199853426e8b3862f618c348e2
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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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