Microbiome-derived bile acids and association with dietary fiber intake to anti-tumor responses in patients with melanoma receiving immune checkpoint blockade (ICB).

Abstract

9575 Background: Multiple studies have now linked high fiber diet (HFD) and outcomes with ICBs, however, the clinical actionability and mechanistic basis of this association remain incompletely defined. We investigated whether microbiome-derived metabolites may function as potentially actionable mediators of this interaction. Methods: Blood samples from two studies in patients (pts) with melanoma starting ICB were utilized: (1) longitudinal samples from the prospective Phase II DIET clinical trial (NCT04645680), in which pts with melanoma starting ICBs were randomized (2:1) to a HFD [up to 50 g fiber/day (d)] or a healthy control diet (HCD, 20 g/d) and (2) baseline samples from an observational prospective diet/microbiome ICB-treated melanoma cohort. Untargeted and targeted metabolome analysis of bile acids and tryptophan-metabolites were performed via liquid chromatography (LC)- and short-chain fatty acids (SCFAs) via gas chromatography (GC)-mass spectrometry. Circulating metabolite levels were compared between pre- and on-treatment samples in DIET trial by arm and between pts with response (R, assessed by RECIST 1.1) and no response (NR) in the observational cohort. Results: A total of 110 pts were included: 45 DIET study pts randomized to HFDI (n=30) vs HCD (n=15), and 65 pts in the observational cohort. As previously reported, response rates were numerically improved in HFD (77% vs 29% in HCD (p=0.06), in the DIET study. Untargeted metabolomics yielded 38 metabolites with statistically significant differences (nominal p<0.05) in change over time in the HFD arm vs in the HCD arm, with notable reductions in glycine conjugated bile acids with HFD. Bile acid biosynthesis metabolite sets were the most significantly differentially enriched (p<0.01, enrichment ratio >5.0). Targeted metabolomics showed that HFD reduced secondary-to-primary bile acid ratios (deoxycholic acid [DCA] to cholic acid [CA], p=0.02) as well as glycine- and taurine-conjugated to unconjugated bile acid ratios (glycocholic acid [GCA] to CA, taurocholic acid [TCA] to CA, both p=0.03). In the observational cohort, GCA/CA and TCA/CA ratios were significantly lower in R vs NR (p=0.03 and p=0.04, respectively) whereas no difference was seen in DCA/CA ratios. SCFAs and tryptophan metabolites showed neither temporal changes in DIET trial nor response associations in the observational cohort. Conclusions: We observed that bile acid deconjugation, a key microbiome-mediated step, was reduced by an HFD intervention and inversely associated with response to ICB in an observational cohort. Building on prior work demonstrating that additional HFD-mediated secondary bile acids can impair T cell function, microbial bile acid metabolism emerges as a potential determinant of anti-tumor response targetable through HFD. Clinical trial information: NCT04645680 .