Loss of NF-kappa B1 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 DW Griffin; Liam O'Connor; Gordon K Smyth; Mathias Ernst; Paul Waring; Steve Gerondakis; Andreas Strasser

Journal article

Loss of NF-kappa B1 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 DW Griffin, Liam O'Connor, Gordon K Smyth Show all

IMMUNITY | CELL PRESS | Published : 2018

DOI: 10.1016/j.immuni.2018.03.003

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 i..

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University of Melbourne Researchers

Lisa Mielke Author Medical Biology (w.e.h.i.)

Paul Waring Author Surgery

Michael Christie Author Clinical Pathology

Tracy Putoczki Author Surgery - Royal Melbourne Hospital

Andrew Kueh Author Medical Biology (w.e.h.i.)

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Grants

Awarded by Cancer Council New South Wales

Awarded by NHMRC; Canberra

Awarded by Worldwide Cancer Research project

Awarded by Independent Research Institutes Infrastructure Support Scheme Grant

Awarded by Leukemia and Lymphoma Society (SCOR grant)

Awarded by JDRF/NHMRC

Funding Acknowledgements

We thank T. Burgess, J. Silke, P. Bouillet, and D. Wortherly for discussions and critical reading of this manuscript, K. Lawlor for advice on flow cytometry, S. Infantino for advice on phospho-flow analysis, G. Siciliano, K. Hughes, and H. Johnston for animal care, B. Helbert, C. Young, and K. Mackwell for genotyping, E. Tsui, B. Tsui, V. Babo, and K. Weston for preparation of histological sections. This work was principally supported by a Cancer Australia and Cancer Council New South Wales project grant #1047672 (L.A.O'R., T.L.P., P.W., M.J.H.). This work was further supported by fellowships and grants from the NHMRC; Canberra; program #1016701 (A.S.), # 1055618 (G.K.S.), fellowships; #1020363 (A.S.), #1058892 (G.S.), #606476 and #1079904 (R.L.F.), and project grants; #1046010 (A.S.), #1008614, #1080498 (T.L.P.), and #603713 (R. Gugasyan), WEHI Dyson Bequest Centenary Fellowship (T.L.P.), Victorian Cancer Agency Fellowship (T.L.P.), Worldwide Cancer Research project grant 14-1197 (T.L.P.), Operational Infrastructure Support Program (Hudson Institute) Australian Postgraduate Award (J.T.L.), Top-up Scholarship, Cancer Therapeutics CRC (Australia) (J.T.L.), and an NHMRC infrastructure grant, Independent Research Institutes Infrastructure Support Scheme Grant #361646, the Victorian State Government (OIS grant), the Leukemia and Lymphoma Society (SCOR grant #7413 and #7001-13) and the JDRF/NHMRC #466658 (A.S.), Monash University Faculty of Medicine, Nursing and Health Sciences Outside Studies Program (R.L.F.).