Mechanisms of immune checkpoint inhibitor-induced gastrointestinal toxicities

Monoclonal antibodies against immune checkpoints such as CTLA-4 and PD-1/PD-L1 have improved response and survival outcomes in advanced melanoma. While improving anti-tumour responses, they can also give rise to atypical inflammatory side effects known as immune-related adverse events (irAEs). Gastrointestinal irAEs, mainly colitis can lead to significant morbidity and cessation of treatment. It is important to identify characteristics and potential mechanisms of colitis to guide treatments without compromising their outcomes. Therefore, the thesis aimed to define the characteristics of colitis and identify mechanisms involved in pathogenesis. A cohort of melanoma patients treated with combination (anti-CTLA-4 with anti-PD-1) or anti-PD-1 monotherapy was retrospectively reviewed for clinical outcomes of colitis. Experimental techniques such as multiplex fluorescence immunohistochemistry, quantitative histopathology on formalin-fixed paraffin-embedded (FFPE) colon biopsy specimens as well as mass cytometry analysis of peripheral blood mononuclear cells (PBMCs) were employed. Mass cytometry analysis of PBMCs shows that the systemic innate immune profile at baseline of colitis patients was distinct with significantly increased monocytes and decreased NK cell subsets. Comprehensive immune phenotyping of paired colon biopsy specimens shows a possible role for tissue-resident memory T cells, Th1 cells, and cells of monocyte-macrophage lineage in the pathogenesis of immune-mediated colitis. The thesis highlights that the systemic immunological changes associated with colitis were independent of anti-tumour responses. The thesis has also examined the differences between combination therapy-induced and monotherapy-induced colitis and found treatment-specific features. Together the data generated from this thesis will provide a strong platform for future studies to identify specific treatment targets for irAEs and biomarkers to predict who is likely to develop irAEs