Microbiome-immune interactions in immune checkpoint inhibitor immunotherapy

Abstract

ICI immunotherapies have revolutionised the treatment of melanoma, although drug resistance or concurrent immune-related adverse events (irAEs) still impact many patients. Growing evidence supports a role for the gut microbiota in shaping both anti-tumour immunity and irAE development. However, previous studies have lacked consensus over the key microbial drivers. This thesis therefore aimed to better understand how microbiome-immune interactions influence the efficacy and safety of therapy. We first profiled the baseline gut microbiome and dietary patterns of 103 Australian and Dutch melanoma patients treated with neo-adjuvant ICIs and performed an integrated analysis with an additional 115 US patients. We found that a patient’s baseline microbiome is associated with both response and the risk of developing irAEs. Specifically, that diet-driven microbial ecology underpins associations between gut microbes and clinical outcomes. Higher rates of response were linked with Ruminococcaceae-dominated gut microbiomes and higher fibre intake, while Bacteroidaceae-dominated microbiomes were associated with a greater risk of early, severe irAEs. We then assessed longitudinal microbiome-immune dynamics during treatment. ICI immunotherapy did not significantly alter the overall composition of the gut microbiome, although larger fluctuations in the gut microbiota were associated with irAE development and non-response suggesting ecological stability may be linked to clinical outcomes. Peripheral immune populations and their dynamics were also associated with clinical outcomes and in part linked with the gut microbiota. Finally, we provide pre-clinical evidence that diet can rapidly alter the gut microbiota and lead to changes in systemic immune tone. Together this thesis illustrates the influence of the gut microbiome on response and irAE development during ICI immunotherapy, highlighting a path for novel approaches targeting the gut microbiota to improve patient outcomes.