A Genome-Wide Screen Identifies Common Variants Accounting For Inter-Individual Differences In Toll-Like Receptor 2 Signaling

Author(s):  
Carmen Mikacenic ◽  
Alexander P. Reiner ◽  
Tarah Holden ◽  
Deborah Nickerson ◽  
Mark M. Wurfel
Cancers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 4782
Author(s):  
Jacqueline E Mann ◽  
Megan L Ludwig ◽  
Aditi Kulkarni ◽  
Erin B Scheftz ◽  
Isabel R Murray ◽  
...  

As immunotherapies targeting the PDL1 checkpoint have become a mainstay of treatment for a subset of head and neck squamous cell carcinoma (HNSCC) patients, a detailed understanding of the mechanisms underlying PDL1-mediated immune evasion is needed. To elucidate factors regulating expression of PDL1 in HNSCC cells, a genome-wide CRISPR profiling approach was implemented to identify genes and pathways conferring altered PDL1 expression in an HNSCC cell line model. Our screen nominated several candidate PDL1 drivers, including Toll-like Receptor 2 (TLR2). Depletion of TLR2 blocks interferon-γ-induced PDL1 expression, and stimulation of TLR2 with either Staphylococcus aureus or a bacterial lipopeptide mimetic, Pam3CSK4, enhanced PDL1 expression in multiple models. The data herein demonstrate a role for TLR2 in modulating the expression of PDL1 in HNSCC models and suggest that microbiota may directly modulate immunosuppression in cancer cells. Our study represents a step toward disentangling the diverse pathways and stimuli regulating PDL1 expression in HNSCC and underscores a need for future work to characterize the complex microbiome in HNSCC patients treated with immunotherapy.


2011 ◽  
Vol 43 (12) ◽  
pp. 1237-1240 ◽  
Author(s):  
Yohei Takahashi ◽  
Ikuyo Kou ◽  
Atsushi Takahashi ◽  
Todd A Johnson ◽  
Katsuki Kono ◽  
...  

2012 ◽  
Vol 15 (3) ◽  
pp. 273-285 ◽  
Author(s):  
Olga Therese Ousdal ◽  
Andrew Anand Brown ◽  
Jimmy Jensen ◽  
Per H. Nakstad ◽  
Ingrid Melle ◽  
...  

As the amygdala is part of the phylogenetic old brain, and its anatomical and functional properties are conserved across species, it is reasonable to assume genetic influence on its activity. A large corpus of candidate gene studies indicate that individual differences in amygdala activity may be caused by genetic variants within monoaminergic signaling pathways such as dopamine, serotonin, and norepinephrine. However, to our knowledge, the use of genome-wide data to discover genetic variants underlying individual differences in adult amygdala activity is novel. In the present study, the combination of genome-wide data and functional imaging phenotypes from an emotional faces task yielded a significant association between rs10014254 and the amygdala using a region of interest approach. This single nucleotide polymorphism is located in a regulatory region upstream of the Paired-like homeobox 2b (PHOX2B) gene; therefore it could affect the expression of this gene. PHOX2B regulates the expression of enzymes necessary for the synthesis of several monoamines and is essential for the development of the autonomic nervous system. However, an attempt to replicate the finding in an independent sample from North America did not succeed. The synthesis of functional magnetic resonance imaging (fMRI) and genome-wide data takes a hypothesis-free approach as to which genetic variants are of interest. Therefore, we believe that an undirected finding within such a plausible region is of interest, and that our results add further support to the hypothesis that monoaminergic signaling pathways play a central role in regulating amygdala activity.


2013 ◽  
Vol 20 (5) ◽  
pp. 765-772 ◽  
Author(s):  
A.-L. Esserlind ◽  
A. F. Christensen ◽  
H. Le ◽  
M. Kirchmann ◽  
A. W. Hauge ◽  
...  

PLoS ONE ◽  
2017 ◽  
Vol 12 (9) ◽  
pp. e0185663 ◽  
Author(s):  
Bendik S. Winsvold ◽  
Francesco Bettella ◽  
Aree Witoelar ◽  
Verneri Anttila ◽  
Padhraig Gormley ◽  
...  

Neurology ◽  
2015 ◽  
Vol 84 (21) ◽  
pp. 2132-2145 ◽  
Author(s):  
R. Malik ◽  
T. Freilinger ◽  
B. S. Winsvold ◽  
V. Anttila ◽  
J. Vander Heiden ◽  
...  

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