Loss of NF-κB1 Causes Gastric Cancer with Aberrant Inflammation and Expression of Immune Checkpoint Regulators in a STAT-1-Dependent Manner

Publication date: 20 March 2018
Source:Immunity, Volume 48, Issue 3
Author(s): Lorraine A. O'Reilly, Tracy L. Putoczki, Lisa A. Mielke, Jun T. Low, Ann Lin, Adele Preaudet, Marco J. Herold, Kelvin Yaprianto, Lin Tai, Andrew Kueh, Guido Pacini, Richard L. Ferrero, Raffi Gugasyan, Yifang Hu, Michael Christie, Stephen Wilcox, Raelene Grumont, Michael D.W. Griffin, Liam O'Connor, Gordon K. Smyth, Mathias Ernst, Paul Waring, Steve Gerondakis, Andreas Strasser
Polymorphisms in NFKB1 that diminish its expression have been linked to human inflammatory diseases and increased risk for epithelial cancers. The underlying mechanisms are unknown, and the link is perplexing given that NF-κB signaling reportedly typically exerts pro-tumorigenic activity. Here we have shown that NF-κB1 deficiency, even loss of a single allele, resulted in spontaneous invasive gastric cancer (GC) in mice that mirrored the histopathological progression of human intestinal-type gastric adenocarcinoma. Bone marrow chimeras revealed that NF-κB1 exerted tumor suppressive functions in both epithelial and hematopoietic cells. RNA-seq analysis showed that NF-κB1 deficiency resulted in aberrant JAK-STAT signaling, which dysregulated expression of effectors of inflammation, antigen presentation, and immune checkpoints. Concomitant loss of STAT1 prevented these immune abnormalities and GC development. These findings provide mechanistic insight into how polymorphisms that attenuate NFKB1 expression predispose humans to epithelial cancers, highlighting the pro-tumorigenic activity of STAT1 and identifying targetable vulnerabilities in GC.

Graphical abstract

Teaser

The links between NF-κB signaling, inflammation, and tumorigenesis are poorly understood. O'Reilly et al. reveal that NF-κB1 deficiency causes gastric cancer by dysregulating inflammation and immune checkpoints through a STAT1-dependent process. This may explain how polymorphisms in NFKB1 that impair its expression predispose to the development of epithelial cancers.


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