Nuclear receptor NR2F6 inhibition potentiates responses to PD-L1/PD-1 cancer immune checkpoint blockade

Analyzing mouse tumor models in vivo, human T cells ex vivo, and human lung cancer samples, we provide direct evidence that NR2F6 acts as an immune checkpoint. Genetic ablation of Nr2f6 , particularly in combination with established cancer immune checkpoint blockade, efficiently delays tumor progres...

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Vydáno v:	Nature communications Ročník 9; číslo 1; s. 1538 - 13
Hlavní autoři:	Klepsch, Victoria, Hermann-Kleiter, Natascha, Do-Dinh, Patricia, Jakic, Bojana, Offermann, Anne, Efremova, Mirjana, Sopper, Sieghart, Rieder, Dietmar, Krogsdam, Anne, Gamerith, Gabriele, Perner, Sven, Tzankov, Alexandar, Trajanoski, Zlatko, Wolf, Dominik, Baier, Gottfried
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London Nature Publishing Group UK 18.04.2018 Nature Publishing Group Nature Portfolio
Témata:	38 38/91 631/67/1059/2325 631/67/1612/1350 631/67/580 64 64/60 96 96/95 Ablation Animal models Animals B7-H1 Antigen - metabolism Biopsy Cancer COUP Transcription Factors - antagonists & inhibitors COUP Transcription Factors - metabolism CTLA-4 protein Deregulation Disease Progression Female Gene Silencing Heterozygote Humanities and Social Sciences Humans Immune checkpoint Immune response Immune System Lung cancer Lymphocytes Lymphocytes T Male Mice Mice, Inbred C57BL multidisciplinary Neoplasm Transplantation Neoplasms - immunology Neoplasms - pathology Non-small cell lung carcinoma PD-1 protein PD-L1 protein Programmed Cell Death 1 Receptor - metabolism Receptors, Steroid - antagonists & inhibitors Receptors, Steroid - metabolism Repressor Proteins RNA, Small Interfering - metabolism Science Science (multidisciplinary) Spleen - metabolism T-Lymphocytes - cytology Transcription Tumors Up-Regulation
ISSN:	2041-1723, 2041-1723
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Shrnutí:	Analyzing mouse tumor models in vivo, human T cells ex vivo, and human lung cancer samples, we provide direct evidence that NR2F6 acts as an immune checkpoint. Genetic ablation of Nr2f6 , particularly in combination with established cancer immune checkpoint blockade, efficiently delays tumor progression and improves survival in experimental mouse models. The target genes deregulated in intratumoral T lymphocytes upon genetic ablation of Nr2f6 alone or together with PD-L1 blockade reveal multiple advantageous transcriptional alterations. Acute Nr2f6 silencing in both mouse and human T cells induces hyper-responsiveness that establishes a non-redundant T-cell-inhibitory function of NR2F6. NR2F6 protein expression in T-cell-infiltrating human NSCLC is upregulated in 54% of the cases ( n = 303) and significantly correlates with PD-1 and CTLA-4 expression. Our data define NR2F6 as an intracellular immune checkpoint that suppresses adaptive anti-cancer immune responses and set the stage for clinical validation of targeting NR2F6 for next-generation immuno-oncological regimens. Immune checkpoints blockade (ICB) is a viable anti-cancer strategy. Here the authors show that nuclear receptor NR2F6 acts as an immune checkpoint in T cells and, using mouse models and human T cells, they show NR2F6 inhibition might improve current ICB therapy or work as an alternative therapeutic strategy.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-018-04004-2