Immune checkpoint inhibitors (CPI) including antibodies targeting CTLA-4 and PD-1, enhance T-cell responses against tumour cells, and have transformed cancer outcomes. However, their success is hampered by autoimmune- like events including CPI-induced colitis, occurring in up to 43%. CPI-colitis incurs significant morbidity, and frequently necessitates permanent CPI discontinuation. Current immunosuppressive treatments, including corticosteroids, cause significant side effects and may diminish CPI efficacy. While interferon gamma (IFNg) responses are characteristically enriched in CPI-colitis, there are concerns IFNg blockade might impede anti-tumour efficacy. A better understanding of this evolving mucosal disease is required to identify alternative therapeutic targets for preclinical testing in CPI-colitis.

Transcriptomic profiling of colonic tissue from CPI-colitis patients revealed marked enrichment of IFNg response complementing previous research. Additionally, there was upregulation of IL-1B and IL-27 pathways, accompanied by enrichment of monocytes, which typically produce these cytokines. Correspondingly, serum IL-27 levels were elevated in CPI-colitis patients.

Immunophenotyping of a preclinical CPI-colitis model using flow cytometry, demonstrated that early disease is associated with increased recruitment of Ly6C+ monocytes to the colon, a reduction in macrophages and dendritic cells and a subtle expansion of polyfunctional TNFa and IFNg producing T-cells. IL-1B and IL-27 pathways were also upregulated at the transcriptomic level.

IL-1B signalling was shown to be dispensable to disease in CPI-colitis mice. However, IL-27 signalling has a context specific role, serving as a functionally important activator of innate immune responses, while inhibiting later phases of acquired immunity via suppressing cytotoxic lymphocyte responses.

This thesis also included the development of a novel 3D colonic organoid model using biopsies from CPI-colitis patients. Preliminary data suggests these organoids conserve an IFNg responsive signature, and that JAK-STAT inhibition with upadacitinib could rescue IFNg induced organoid damage.