LAUSR

Studies have demonstrated promising outcomes of combined immune checkpoint blockade (CICB) modulating tumor cytotoxicity via targeting cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death 1 (PD-1). The emergence of long-term patient management has been transformed among health care professionals as patient survival rates are increasing significantly. Despite promising advances, patient outcomes are heterogenic and are correlative to host intrinsic and extrinsic factors. Multiple reports have highlighted the negative effects of cancer treatments towards inducing cognitive impairment and neurotoxicity often referred to as “chemofog”. More recently, the gut microbiome has been increasingly recognized to regulate antitumor immunity and further distinct microbiome signatures can confer favorable outcomes in the context of CICB. Interestingly, specific microbes within the gut microbiome have been shown to regulate social behavior and cognition via the bidirectional communication along the gut-brain axis though changes in microbiota-derived metabolites and vagal afferent fibers. Insights into mechanisms of immunotherapy induced cognitive decline are warranted. Thus, we hypothesize CICB exacerbates cognitive impairment and neurotoxicity via the detrimental alterations to the gut microbiome. To address this, we profiled the gut microbiome, through 16S rRNA gene and metagenomic sequencing of fecal samples from patients (n=146) with advanced melanoma treated with CICB stratified based on severity of cognitive dissonance. Beta-diversity, incorporating weighted UniFrac distances by principal coordinate analysis (PCoA), revealed a cluster of samples from patients with cognitive impairment as compared to samples from those with minimal to absent cognitive decline. Further, taxonomical analysis showed significant alterations in relative abundances of microbial candidates (e.g., L. intestinalis, A. muciniphila, F. prausnitizii, and R. hominis). These results suggests that CICB patients with cognitive impairments and neurotoxicity have altered microbiome signatures which may potentially exacerbate downstream neuroinflammatory signaling. Further studies investigating specific host-microbe pathways and profiling microbiota-derived metabolites which are implicated in these detrimental effects are essential for biomarker discovery and mechanistic insight. Citation Format: Anik Banerjee, Christina Roland, Sarah Johnson, Nadim Ajami, Jennifer Wargo. Gut microbiota signatures are associated with immunotherapy induced cognitive decline and neurotoxicity. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5906.