dc.date.accessioned | 2018-06-12T09:17:40Z | |
dc.date.available | 2018-12-07T23:31:50Z | |
dc.date.created | 2017-12-13T10:28:21Z | |
dc.date.issued | 2017 | |
dc.identifier.citation | Josefsson, Sarah Elisabet Göthberg Huse, Kanutte Kolstad, Arne Beiske, Klaus Pende, Daniela Steen, Chloe Beate Inderberg, Else Marit Lingjærde, Ole Christian Østenstad, Bjørn Smeland, Erlend B Levy, Ronald Irish, Jonathan M. Myklebust, June . T cells expressing checkpoint receptor TIGIT are enriched in follicular lymphoma tumors and characterized by reversible suppression of T-cell receptor signaling. Clinical Cancer Research. 2017 | |
dc.identifier.uri | http://hdl.handle.net/10852/61853 | |
dc.description.abstract | Purpose: T cells infiltrating follicular lymphoma (FL) tumors are considered dysfunctional, yet the optimal target for immune checkpoint blockade is unknown. Characterizing coinhibitory receptor expression patterns and signaling responses in FL T-cell subsets might reveal new therapeutic targets.
Experimental Design: Surface expression of 9 coinhibitory receptors governing T-cell function was characterized in T-cell subsets from FL lymph node tumors and from healthy donor tonsils and peripheral blood samples, using high-dimensional flow cytometry. The results were integrated with T-cell receptor (TCR)-induced signaling and cytokine production. Expression of T-cell immunoglobulin and ITIM domain (TIGIT) ligands was detected by immunohistochemistry.
Results: TIGIT was a frequently expressed coinhibitory receptor in FL, expressed by the majority of CD8 T effector memory cells, which commonly coexpressed exhaustion markers such as PD-1 and CD244. CD8 FL T cells demonstrated highly reduced TCR-induced phosphorylation (p) of ERK and reduced production of IFNγ, while TCR proximal signaling (p-CD3ζ, p-SLP76) was not affected. The TIGIT ligands CD112 and CD155 were expressed by follicular dendritic cells in the tumor microenvironment. Dysfunctional TCR signaling correlated with TIGIT expression in FL CD8 T cells and could be fully restored upon in vitro culture. The costimulatory receptor CD226 was downregulated in TIGIT+ compared with TIGIT− CD8 FL T cells, further skewing the balance toward immunosuppression.
Conclusions: TIGIT blockade is a relevant strategy for improved immunotherapy in FL. A deeper understanding of the interplay between coinhibitory receptors and key T-cell signaling events can further assist in engineering immunotherapeutic regimens to improve clinical outcomes of cancer patients. | en_US |
dc.language | EN | |
dc.title | T cells expressing checkpoint receptor TIGIT are enriched in follicular lymphoma tumors and characterized by reversible suppression of T-cell receptor signaling | en_US |
dc.type | Journal article | en_US |
dc.creator.author | Josefsson, Sarah Elisabet Göthberg | |
dc.creator.author | Huse, Kanutte | |
dc.creator.author | Kolstad, Arne | |
dc.creator.author | Beiske, Klaus | |
dc.creator.author | Pende, Daniela | |
dc.creator.author | Steen, Chloe Beate | |
dc.creator.author | Inderberg, Else Marit | |
dc.creator.author | Lingjærde, Ole Christian | |
dc.creator.author | Østenstad, Bjørn | |
dc.creator.author | Smeland, Erlend B | |
dc.creator.author | Levy, Ronald | |
dc.creator.author | Irish, Jonathan M. | |
dc.creator.author | Myklebust, June | |
cristin.unitcode | 185,15,5,35 | |
cristin.unitname | Forskningsgruppen for biomedisinsk informatikk | |
cristin.ispublished | true | |
cristin.fulltext | postprint | |
cristin.qualitycode | 2 | |
dc.identifier.cristin | 1526606 | |
dc.identifier.bibliographiccitation | info:ofi/fmt:kev:mtx:ctx&ctx_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.jtitle=Clinical Cancer Research&rft.volume=&rft.spage=&rft.date=2017 | |
dc.identifier.jtitle | Clinical Cancer Research | |
dc.identifier.doi | http://dx.doi.org/10.1158/1078-0432.CCR-17-2337 | |
dc.identifier.urn | URN:NBN:no-64453 | |
dc.type.document | Tidsskriftartikkel | en_US |
dc.type.peerreviewed | Peer reviewed | |
dc.source.issn | 1078-0432 | |
dc.identifier.fulltext | Fulltext https://www.duo.uio.no/bitstream/handle/10852/61853/1/1078-0432.CCR-17-2337.full.pdf | |
dc.type.version | AcceptedVersion | |
dc.relation.project | NFR/179571 | |
dc.relation.project | KF/33550 | |