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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Published in:Nature communications Vol. 9; no. 1; pp. 1538 - 13
Main Authors: 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
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 18.04.2018
Nature Publishing Group
Nature Portfolio
Subjects:
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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
Online Access:Get full text
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Summary: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.
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-018-04004-2