Targeting Ewing sarcoma with activated and GD2-specific chimeric antigen receptor-engineered human NK cells induces upregulation of immune-inhibitory HLA-G

Kailayangiri S., Altvater B., Spurny C., Jamitzky S., Schelhaas S., Jacobs A., Wiek C., Roellecke K., Hanenberg H., Hartmann W., Wiendl H., Pankratz S., Meltzer J., Farwick N., Greune L., Fluegge M., Rossig C.

Research article (journal) | Peer reviewed

Abstract

Activated and in vitro expanded natural killer (NK) cells have substantial cytotoxicity against many tumor cells, but their in vivo efficacy to eliminate solid cancers is limited. Here, we used chimeric antigen receptors (CARs) to enhance the activity of NK cells against Ewing sarcomas (EwS) in a tumor antigen-specific manner. Expression of CARs directed against the ganglioside antigen GD2 in activated NK cells increased their responses to GD2+ allogeneic EwS cells in vitro and overcame resistance of individual cell lines to NK cell lysis. Second-generation CARs with 4-1BB and 2B4 co-stimulatory signaling and third-generation CARs combining both co-stimulatory domains were all equally effective. By contrast, adoptive transfer of GD2-specific CAR gene-modified NK cells both by intratumoral and intraperitoneal delivery failed to eliminate GD2-expressing EwS xenografts. Histopathology review revealed upregulation of the immunosuppressive ligand HLA-G in tumor autopsies from mice treated with NK cells compared to untreated control mice. Supporting the relevance of this finding, in vitro co-incubation of NK cells with allogeneic EwS cells induced upregulation of the HLA-G receptor CD85j, and HLA-G1 expressed by EwS cells suppressed the activity of NK cells from three of five allogeneic donors against the tumor cells in vitro. We conclude that HLA-G is a candidate immune checkpoint in EwS where it can contribute to resistance to NK cell therapy. HLA-G deserves evaluation as a potential target for more effective immunotherapeutic combination regimens in this and other cancers.

Details about the publication

JournalOncoImmunology
Volumenull
Issuenull
Statusonline first
Release year2016
Language in which the publication is writtenEnglish
DOI10.1080/2162402X.2016.1250050
Link to the full texthttps://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85008144025&origin=inward
KeywordsChimeric antigen receptors; Ewing sarcoma; HLA-G; inhibitory immune checkpoints; NK cells

Authors from the University of Münster

Eichler, Susann
Department for Neurology
Hartmann, Wolfgang
Gerhard Domagk Institute of Pathology
Rössig, Claudia
University Children's Hospital - Department of Paediatric Haematology and Oncology (UKM PHO)
Wiendl, Heinz Siegfried
Department for Neurology