Abstract 2861: Comparative genomics of gut commensal <i>Lachnospiraceae</i> and their associations with cancer treatment response with immune checkpoint inhibitors

Abstract Immune checkpoint inhibitors (ICIs) are seminal advances in cancer therapeutics, yet response rates are variable. The gut microbiome is increasingly recognized as a modifiable determinant of ICI efficacy. The BEWELL trial delivered a black raspberry (BRB) nectar dietary intervention that significantly enriched the colonic microbiome with members of the Lachnospiraceae family. When BRB-modulated microbiomes were transferred into mice, these microbiomes enhanced ICI antitumor activity, implicating specific taxa in shaping therapeutic responsiveness.To investigate the mechanism by which Lachnospiraceae altered ICI effectiveness, we individually supplemented the microbiomes of mice with closely related strains enriched by BRB: Blautia obeum, Blautia massiliensis, and Agathobacter rectalis. In a heterotopic mouse model (1×106 MC38 cells injected subcutaneously into C57BL/6 mice, treated every 3 days with anti-PD1 or IgG), B. obeum and B. massiliensis improved ICI effectiveness, whereas A. rectalis did not. We compared the genomes of these organisms and identified 177 KEGG orthologs uniquely shared by B. obeum and B. massiliensis but absent in A. rectalis. KO pathway assignments and enrichment analyses were conducted using KEGGREST mapping and clusterProfiler overrepresentation testing, with all genome-encoded KOs as the background.We identified four relevant pathways associated with immunity and ICI response:(1) Key genes for the Wood-Ljungdahl pathway, a major route for producing acetate, shown to be a T-cell energy source (acetyl-CoA decarbonylase/synthase (K00194, K00197, K00198) and putative phosphotransacetylase (K01490));(2) Genes for synthesizing vitamins essential for T-cell proliferation—folate (B9) (dihydropteroate synthase (K00796), GTP cyclohydrolase I (K022391), methylenetetrahydrofolate reductase (K00297)) and cobalamin (B12) (cob(I)alamin adenosyltransferase (K019221), corrinoid adenosyltransferase (K0174), cobalamin reductase (K0175));(3) L-rhamnose synthesis genes whose cell-wall decorations act as microbe-associated molecular patterns, priming innate immunity (dTDP-4-dehydrorhamnose reductase (K00067) and dTDP-glucose 4,6-dehydratase (K00935)); and(4) Genes converting bile acids to secondary, iso-bile acids that interact with host receptors (FXR, TGR5) to regulate Th17/Treg balance (3-alpha-hydroxycholanate dehydrogenase (K0164)) Collectively, these processes align with host-relevant metabolic and signaling environments that may impact anti-tumor immunity. Our study suggests that novel food products can be developed for human testing to enhance anticancer immunotherapeutics. Furthermore, BRB-responsive Lachnospiraceae possess enriched metabolic and immunomodulatory gene programs that may underlie their association with improved tumor response to ICI treatment. Citation Format: Shiva Jahanbakhshi, Amna Bibi, Rebecca Hoyd, Caroline Dravillas, Nyelia Williams, Shiqi Zhang, Aaditya Pallerla, Shankar Suman, Joseph Amann, Mounika Goruganthu, Tamio Okimoto, Yangyang Liu, Marisa A. Bittoni, Ni Shi, Alvin Anand, Bailey Conrad, Lane Nevers, Kristen Heitman, Maxine Webb, Elizabeth M. Grainger, Madison Grogan, Christian Quiles, Tong Chen, Carolyn J. Presley, Lang Li, Patrick Bradley, Yael Vodovotz, David P. Carbone, Steven K. Clinton, Jiangjiang Zhu, Daniel Spakowicz, . Comparative genomics of gut commensal Lachnospiraceae and their associations with cancer treatment response with immune checkpoint inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2861.