Gastric cancer (GC) is the 3rd highest cause of cancer-related mortality worldwide in 2020. The largely asymptomatic nature of GC tends to result in late-stage diagnosis and current therapies are usually only palliative. One potentially promising strategy to treat GC is Immune Checkpoint Inhibitor Therapy (ICIT), such as CTLA-4, PD-1 or PD-L1 antibodies, which boost the cytotoxic activity of tumour antigen-specific T cells. The full potential of ICIT for GC has not yet been realised because of associated toxicities (irAEs), despite unstratified, trials in GC patients indicating that ICIT might be appropriate for certain molecular subtypes.
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 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. Nfkb1-/-mice align molecularly to the subgroups of GC patients which are most likely to respond to ICITs. Mice deficient in NF-kB1 also develop systemic inflammation, mimicking irAEs, such that they are primed for and do develop irAEs when treated with single or dual ICITs. The Nfkb1-/- pre-clinical mouse model is therefore uniquely suited to simultaneously trial the most effective combinations of ICIT therapies to treat GC and develop strategies to limit irAEs.