SUMMARY
Anti-tumor immunity varies due to interactions between innate and adaptive immune cells, microbial
community diversity, host and microbially derived metabolites, and other local factors that shape tumoricidal
responses. While most of the recent microbiome research focuses on the gut microbiome and cancer
outcomes, extra-intestinal microbial communities are detected in the tumor microenvironment (TME). We
recently reported that specific microbes identified in patient breast tumors compared to pathologically normal
breast samples associated with tumor stage, tumor subtype, and for the first time, race. Triple Negative Breast
Cancer (TNBC), an aggressive subtype that has generally eluded personalized medicine approaches,
contained unique microbes that may mediate immunosuppression and impact standard chemotherapy or
immune checkpoint inhibitor (ICI) efficacies. Yet to date, mechanisms underpinning these observations are
unresolved as to how the gut and/or extra-intestinal microbiome influence BC onset, progression, and
response to therapies, which is a major knowledge gap in this field. One cogent mechanism that may link
microbes to anti-tumor immunity are microbially modified metabolites, namely bile acids. Certain microbes rich
in 7-alpha-hydroxylase convert primary to secondary bile acids which regulate bile acid composition. Bile acids
have been shown to limit progression and metastasis in other cancers through reversing immunosuppression,
but minimal work has explored the role of bile acids in BC. Bile acids signal through several bile acid receptors
including farnesoid X receptor (FXR). We posit that specific gut or local resident microbes that impact bile acid
pools and composition will interact with cells expressing FXR to regulate the TME immune milieu. We report for
the first time that patients with high FXR expression have greater relapse-free survival uniquely in TNBC
subtype, but not in less aggressive luminal BC subtype, suggesting potential for targeted approaches. The
overall objective of this proposal is to test mechanisms linking Microbes¿Bile Acids¿TNBC which poses an
opportunity to generate novel therapeutics and precision medicine informed by microbial compositions. Our
innovative approach interrogates targetable microbial pathways that we demonstrate change the microbiome,
bile acids, and tumor progression. Our central hypothesis is microbial composition and microbially-modified
metabolic products, such as bile acids, increase immunotherapeutic efficacy through reprogramming the TME
leading to enhanced anti-tumor immunity. We will test our hypothesis by performing the following aims: 1)
Determine if commensal microbes play a physiological role in TNBC anti-tumor immunity; 2) Determine if the
microbiome alters immunosurveillance of early tumor onset and progression; 3) Determine if pharmacologic
bile acid receptor agonism improves TNBC immunotherapy. Findings generated will have high impact because
the lack of targeted therapies for TNBC presents a great unmet clinical need and could be transformative to
improve patient outcomes.