dc.contributor.author
Toews, Karin
dc.contributor.author
Grunewald, Laura
dc.contributor.author
Schwiebert, Silke
dc.contributor.author
Klaus, Anika
dc.contributor.author
Winkler, Annika
dc.contributor.author
Ali, Solin
dc.contributor.author
Zirngibl, Felix
dc.contributor.author
Astrahantseff, Kathy
dc.contributor.author
Wagner, Dimitrios L.
dc.contributor.author
Henssen, Anton G.
dc.contributor.author
Deubzer, Hedwig E.
dc.contributor.author
Schulte, Johannes H.
dc.contributor.author
Ochsenreither, Sebastian
dc.contributor.author
Eggert, Angelika
dc.contributor.author
Künkele, Annette
dc.date.accessioned
2022-03-03T13:51:44Z
dc.date.available
2022-03-03T13:51:44Z
dc.identifier.uri
https://refubium.fu-berlin.de/handle/fub188/34316
dc.identifier.uri
http://dx.doi.org/10.17169/refubium-34033
dc.description.abstract
The immunosuppressive microenvironment in solid tumors is thought to form a barrier to the entry and efficacy of cell-based therapies such as chimeric antigen receptor (CAR) T cells. Combining CAR T cell therapy with checkpoint inhibitors has been demonstrated to oppose immune escape mechanisms in solid tumors and augment antitumor efficacy. We evaluated PD-1/PD-L1 signaling capacity and the impact of an inhibitor of this checkpoint axis in an in vitro system for cancer cell challenge, the coculture of L1CAM-specific CAR T cells with neuroblastoma cell lines. Fluorescence-activated cell sorting-based analyses and luciferase reporter assays were used to assess PD-1/PD-L1 expression on CAR T and tumor cells as well as CAR T cell ability to kill neuroblastoma cells. Coculturing neuroblastoma cell lines with L1CAM-CAR T cells upregulated PD-L1 expression on neuroblastoma cells, confirming adaptive immune resistance. Exposure to neuroblastoma cells also upregulated the expression of the PD-1/PD-L1 axis in CAR T cells. The checkpoint inhibitor, nivolumab, enhanced L1CAM-CAR T cell-directed killing. However, nivolumab-enhanced L1CAM-CAR T cell killing did not strictly correlate with PD-L1 expression on neuroblastoma cells. In fact, checkpoint inhibitor success relied on strong PD-1/PD-L1 axis expression in the CAR T cells, which in turn depended on costimulatory domains within the CAR construct, and more importantly, on the subset of T cells selected for CAR T cell generation. Thus, T cell subset selection for CAR T cell generation and CAR T cell prescreening for PD-1/PD-L1 expression could help determine when combination therapy with checkpoint inhibitors could improve treatment efficacy.
en
dc.rights.uri
https://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject
central memory T cells
en
dc.subject
chimeric antigen receptor T cell therapy
en
dc.subject
microenvironment
en
dc.subject.ddc
600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::610 Medizin und Gesundheit
dc.title
Central memory phenotype drives success of checkpoint inhibition in combination with CAR T cells
dc.type
Wissenschaftlicher Artikel
dcterms.bibliographicCitation.doi
10.1002/mc.23202
dcterms.bibliographicCitation.journaltitle
Molecular Carcinogenesis
dcterms.bibliographicCitation.number
7
dcterms.bibliographicCitation.originalpublishername
Wiley
dcterms.bibliographicCitation.pagestart
724
dcterms.bibliographicCitation.pageend
735
dcterms.bibliographicCitation.volume
59
refubium.affiliation
Charité - Universitätsmedizin Berlin
refubium.funding
DEAL Wiley
refubium.resourceType.isindependentpub
no
dcterms.accessRights.openaire
open access
dcterms.bibliographicCitation.pmid
32333465
dcterms.isPartOf.issn
0899-1987
dcterms.isPartOf.eissn
1098-2744