NF-kB activation and STAT signaling are both recognized as important drivers of inflammation-associated cancers. Notably, polymorphisms in NFKB1 that diminish its expression have been linked to multiple human inflammatory diseases and increased risk for epithelial cancers. We have recently shown that NF-kB1 deficiency, even loss of a single allele, results in spontaneous invasive gastric cancer (GC) in mice that mirror the histopathological progression of human intestinal-type gastric adenocarcinoma. RNA-seq showed that NF-kB1 deficiency resulted in aberrant JAK-STAT signaling, which dysregulated expression of effectors of inflammation, including antigen presentation and immune checkpoint regulators. Concomitant loss of STAT1 prevented these immune abnormalities, significantly increasing survival and preventing GC development. Our findings provide mechanistic insight into how polymorphisms that attenuate NFKB1 expression predispose humans to epithelial cancers and a functional link between loss of NF-kB1, aberrant STAT1 activation and increased PD-L1, a link also seen in the EBV+ subtype of human GC.
Our studies further highlight a pro-tumorigenic activity for STAT1 and identify targetable vulnerabilities in GC, such as immune checkpoints. Since immune checkpoint inhibitor therapies (ICIT) are currently in their infancy for human GC, our Nfkb1-/- pre-clinical mouse model can be used to trial the most effective therapies, whilst also providing insight into the causes and treatment options for the associated toxicities (irAEs).