Gastric cancer (GC) is the 6th most common cancer and is the 3rd highest cause of cancer-related mortality worldwide. One potentially promising strategy to treat GC is Immune Checkpoint Inhibitor Therapy (ICIT). The full potential of ICIT has not yet been realised because it can also induce systemic inflammatory toxicities (irAEs).
We have developed a pre-clinical cancer model in Nfkb1 deficient mice, that faithfully mimics the molecular, histopathological and invasive features of human GC. Critically, human NFKB1 polymorphisms that reduce NFkB1 function have been linked to increased risk in GC and align molecularly with the ~35% of GC patients (Epstein-Barr virus - EBV+ or MicroSatellite Instability - MSI+) most likely to respond to ICIT.
Our Nfkb1-/- and accelerated GC model Nfkb1-/-;gp130Y757F/+ also exhibit mild multi-organ auto-immunity in the absence of ICIT. However, we have shown that classical irAEs markers, such as immune cell infiltration of organs are found in these models after anti-PD-L1 and particularly after dual agent ICIT treatment (anti-PD-L1 plus anti-CTLA-4 treatment).
Our GC model is ideally suited to assess simultaneously both the efficacy of ICIT and, uniquely for mouse models, to investigate ICIT induced irAEs and how they may be combated, such as by Cytokine-based immunotherapy, which will be discussed.