Abstract 6681: Altered microbial community stability and increases in circulating B cells are associated with the development of severe immune related adverse events during ICI-immunotherapy

Abstract Background: Immune related adverse events (irAEs) are a major hurdle to the success of immune checkpoint inhibitor (ICI) immunotherapy. There is increasing evidence that the gut microbiota influences irAE development, however the microbe-immune crosstalk underpinning this remains cryptic. Methods: Paired pre- 0. 0001) and an increase in activated B cells subsets (CD27- CD38- CD24- populations) (P=0. 0022) were observed between baseline and week 6 across all patients who developed or went on to develop severe irAEs. Most notably, Ba patients who developed early, severe irAEs specifically had significantly higher frequencies of overall circulating B cells (P=0. 0018) and lower frequencies of ICOS+ Tregs at week 6 post treatment (P=0. 0005), which was not observed in Ru-dominated irAE patients. Conclusions: Higher risk of early, severe irAEs were associated with Bacteroidaceae-dominated gut microbiomes, reduced microbial community stability, and increases in activated circulating B cells during treatment. We postulate that differing baseline microbial community assemblages are associated with altered pre-established intestinal homeostasis influencing the likelihood of irAE development. Together, the data highlights a potential relationship between B cells, the gut microbiota and irAE development which may point to early steps in the induction of irAEs during ICI immunotherapy. Citation Format: Rebecca C. Simpson, Erin R. Shanahan, Ines P. Silva, Irene L. Reijers, Judith M. Versluis, Alexander M. Menzies, Gonzalez Maria, Umaimainthan Palendira, James S. Wilmott, Christian Blank, Richard A. Scolyer, Georgina V. Long. Altered microbial community stability and increases in circulating B cells are associated with the development of severe immune related adverse events during ICI-immunotherapy abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 6681.