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

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 & 4 others Mathias Ernst, Paul Waring, Steve Gerondakis, Andreas Strasser

Research output: Contribution to journalArticleResearchpeer-review

14 Citations (Scopus)

Abstract

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. 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.

Original languageEnglish
Pages (from-to)570-583
Number of pages14
JournalImmunity
Volume48
Issue number3
DOIs
Publication statusPublished - 20 Mar 2018

Cite this

O'Reilly, L. A., Putoczki, T. L., Mielke, L. A., Low, J. T., Lin, A., Preaudet, A., ... Strasser, A. (2018). Loss of NF-κB1 Causes Gastric Cancer with Aberrant Inflammation and Expression of Immune Checkpoint Regulators in a STAT-1-Dependent Manner. Immunity, 48(3), 570-583. https://doi.org/10.1016/j.immuni.2018.03.003
O'Reilly, Lorraine A. ; Putoczki, Tracy L. ; Mielke, Lisa A. ; Low, Jun T. ; Lin, Ann ; Preaudet, Adele ; Herold, Marco J. ; Yaprianto, Kelvin ; Tai, Lin ; Kueh, Andrew ; Pacini, Guido ; Ferrero, Richard L. ; Gugasyan, Raffi ; Hu, Yifang ; Christie, Michael ; Wilcox, Stephen ; Grumont, Raelene ; Griffin, Michael D.W. ; O'Connor, Liam ; Smyth, Gordon K. ; Ernst, Mathias ; Waring, Paul ; Gerondakis, Steve ; Strasser, Andreas. / Loss of NF-κB1 Causes Gastric Cancer with Aberrant Inflammation and Expression of Immune Checkpoint Regulators in a STAT-1-Dependent Manner. In: Immunity. 2018 ; Vol. 48, No. 3. pp. 570-583.
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abstract = "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. 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.",
author = "O'Reilly, {Lorraine A.} and Putoczki, {Tracy L.} and Mielke, {Lisa A.} and Low, {Jun T.} and Ann Lin and Adele Preaudet and Herold, {Marco J.} and Kelvin Yaprianto and Lin Tai and Andrew Kueh and Guido Pacini and Ferrero, {Richard L.} and Raffi Gugasyan and Yifang Hu and Michael Christie and Stephen Wilcox and Raelene Grumont and Griffin, {Michael D.W.} and Liam O'Connor and Smyth, {Gordon K.} and Mathias Ernst and Paul Waring and Steve Gerondakis and Andreas Strasser",
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O'Reilly, LA, Putoczki, TL, Mielke, LA, Low, JT, Lin, A, Preaudet, A, Herold, MJ, Yaprianto, K, Tai, L, Kueh, A, Pacini, G, Ferrero, RL, Gugasyan, R, Hu, Y, Christie, M, Wilcox, S, Grumont, R, Griffin, MDW, O'Connor, L, Smyth, GK, Ernst, M, Waring, P, Gerondakis, S & Strasser, A 2018, 'Loss of NF-κB1 Causes Gastric Cancer with Aberrant Inflammation and Expression of Immune Checkpoint Regulators in a STAT-1-Dependent Manner', Immunity, vol. 48, no. 3, pp. 570-583. https://doi.org/10.1016/j.immuni.2018.03.003

Loss of NF-κB1 Causes Gastric Cancer with Aberrant Inflammation and Expression of Immune Checkpoint Regulators in a STAT-1-Dependent Manner. / O'Reilly, Lorraine A.; Putoczki, Tracy L.; Mielke, Lisa A.; Low, Jun T.; Lin, Ann; Preaudet, Adele; Herold, Marco J.; Yaprianto, Kelvin; Tai, Lin; Kueh, Andrew; Pacini, Guido; Ferrero, Richard L.; Gugasyan, Raffi; Hu, Yifang; Christie, Michael; Wilcox, Stephen; Grumont, Raelene; Griffin, Michael D.W.; O'Connor, Liam; Smyth, Gordon K.; Ernst, Mathias; Waring, Paul; Gerondakis, Steve; Strasser, Andreas.

In: Immunity, Vol. 48, No. 3, 20.03.2018, p. 570-583.

Research output: Contribution to journalArticleResearchpeer-review

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AU - O'Reilly, Lorraine A.

AU - Putoczki, Tracy L.

AU - Mielke, Lisa A.

AU - Low, Jun T.

AU - Lin, Ann

AU - Preaudet, Adele

AU - Herold, Marco J.

AU - Yaprianto, Kelvin

AU - Tai, Lin

AU - Kueh, Andrew

AU - Pacini, Guido

AU - Ferrero, Richard L.

AU - Gugasyan, Raffi

AU - Hu, Yifang

AU - Christie, Michael

AU - Wilcox, Stephen

AU - Grumont, Raelene

AU - Griffin, Michael D.W.

AU - O'Connor, Liam

AU - Smyth, Gordon K.

AU - Ernst, Mathias

AU - Waring, Paul

AU - Gerondakis, Steve

AU - Strasser, Andreas

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