Symposium Presentation Australian Society for Microbiology Annual Scientific Meeting 2024

Gut microbial ecosystem features associated with cancer immunotherapy outcomes (104600)

Erin Shanahan 1 2 , Rebecca Simpson 2 3 , Ines Silva 3 4 , Irene Reijers 5 , Judith Versluis 5 , Alexander Menzies 3 4 , Maria Gonzales 3 , James Wilmott 3 4 , Christian Blank 5 , Richard Scolyer 3 4 , Georgina Long 3 4
  1. School of Life and Environmental Sciences, The University of Sydney, Camperdown, NSW, Australia
  2. Charles Perkins Centre, The University of Sydney, Camperdown, NSW, Australia
  3. Melanoma Institute Australia, The University of Sydney, Camperdown, NSW, Australia
  4. Sydney Medical School, The University of Sydney, Sydney, NSW, Australia
  5. Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands

A key challenge in the application of gut microbial ecology to address issues of human health is a lack of consensus, in terms of microbial features identified, across studies. This is particularly the case for understanding the role of the gut microbiota in shaping local and systemic immunity. The gut microbiota has recently been implicated in efficacy of immunotherapies for cancer. Immune checkpoint inhibitors (ICIs) are antibodies that block immune checkpoint receptors CTLA-4 and PD-1 and restore anti-tumour immunity. These immunotherapies have recently revolutionised treatment of various cancers. However, despite increased survival rates, not all patients respond to ICI therapy, and immune activation in normal host tissue can result in severe immune-related adverse events (irAEs), including colitis.

We aimed to identify microbial ecosystem features linked to response and protection from irAEs during ICI therapy. We profiled pre-treatment faecal microbiota, dietary patterns and systemic immune phenotypes (PBMCs) in 129 Australian and Dutch patients treated with ICI for metastatic melanoma. Latent class analysis revealed microbial community features with different prevalence across the three cohorts. Stratification of patients into these classes enabled identification of consensus biomarkers. Overall, higher response rates to ICI treatment were seen in patients with Ruminococcaceae-dominated (RUM) microbiomes, which were more diverse, and linked to higher fibre intake. Lower response rates were observed in Bacteroidaceae-dominated (BAC) microbiomes, and these patients were more likely to develop severe, early irAEs. Higher relative abundance of the key gut microbe Faecalibacterium prausnitzii was identified as an important biomarker of response and protection from irAEs, only in patients with BAC microbiomes, but afforded no benefit in RUM patients. Notably, BAC patients with severe irAEs specifically had significantly higher frequencies of circulating B cells and lower frequencies of ICOS+ Tregs post treatment, which was not observed in RUM irAE patients.

Our data suggests the potential for differential immunotherapy response mechanisms linked to pre-existing immune tone and the gut microbiota. These findings highlight the importance of accounting for microbial community ecology when linking gut microbes to human health outcomes.