The gut microbiome enhances breast cancer immunotherapy following bariatric surgery
Margaret S. Bohm, Sydney C. Joseph, Laura M. Sipe, Minjeong Kim, Cameron T. Leathem, Tahliyah S. Mims, Nathaniel B. Willis, Ubaid A. Tanveer, Joel H. Elasy, Emily W. Grey, Madeline E. Pye, Zeid T. Mustafa, Barbara Anne Harper, Logan G. McGrath, Deidre Daria, Brenda Landvoigt Schmitt, Jelissa A. Myers, Patricia Pantoja Newman, Brandt D. Pence, Marie Van der Merwe, Matthew J. Davis, Joseph F. Pierre, Liza Makowski
Margaret S. Bohm, Sydney C. Joseph, Laura M. Sipe, Minjeong Kim, Cameron T. Leathem, Tahliyah S. Mims, Nathaniel B. Willis, Ubaid A. Tanveer, Joel H. Elasy, Emily W. Grey, Madeline E. Pye, Zeid T. Mustafa, Barbara Anne Harper, Logan G. McGrath, Deidre Daria, Brenda Landvoigt Schmitt, Jelissa A. Myers, Patricia Pantoja Newman, Brandt D. Pence, Marie Van der Merwe, Matthew J. Davis, Joseph F. Pierre, Liza Makowski
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Research Article Immunology Microbiology Oncology

The gut microbiome enhances breast cancer immunotherapy following bariatric surgery

Abstract

Bariatric surgery is associated with improved breast cancer (BC) outcomes, including greater immunotherapy effectiveness in a preclinical BC model. A potential mechanism of bariatric surgery–associated protection is the gut microbiota. Here, we demonstrate the dependency of improved immunotherapy response on the post–bariatric surgery gut microbiome via fecal microbiota transplantation (FMT). Response to αPD-1 immunotherapy was significantly improved following FMT from formerly obese bariatric surgery–treated mice. When stool from post–bariatric surgery patients was transplanted into recipient mice and compared to the patients’ presurgery transplants, postsurgery microbes significantly reduced tumor burden and doubled immunotherapy effectiveness. Microbes impact tumor burden through microbially derived metabolites, including branched-chain amino acids (BCAAs). Circulating BCAAs correlated significantly with natural killer T (NKT) cell content in the tumor microenvironment in donor mice after bariatric surgery and FMT recipients of donor cecal content after bariatric surgery compared with obese controls. BCAA supplementation replicated improved αPD-1 effectiveness in 2 BC models, supporting the role of BCAAs in increased immunotherapy effectiveness after bariatric surgery. Ex vivo exposure increased primary NKT cell expression of antitumor cytokines, demonstrating direct activation of NKT cells by BCAAs. Together, the findings suggest that reinvigorating antitumor immunity may depend on bariatric surgery–associated microbially derived metabolites, namely BCAAs.

Authors

Margaret S. Bohm, Sydney C. Joseph, Laura M. Sipe, Minjeong Kim, Cameron T. Leathem, Tahliyah S. Mims, Nathaniel B. Willis, Ubaid A. Tanveer, Joel H. Elasy, Emily W. Grey, Madeline E. Pye, Zeid T. Mustafa, Barbara Anne Harper, Logan G. McGrath, Deidre Daria, Brenda Landvoigt Schmitt, Jelissa A. Myers, Patricia Pantoja Newman, Brandt D. Pence, Marie Van der Merwe, Matthew J. Davis, Joseph F. Pierre, Liza Makowski

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Figure 1

Microbes transplanted from VSG donors improved response to αPD-1 immune checkpoint blockade therapy.

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Microbes transplanted from VSG donors improved response to αPD-1 immune ...
(A) Study schema: Female C57BL/6J mice were purchased from The Jackson Laboratory at 4 weeks of age. On day –13, a broad-spectrum antibiotic cocktail (1 g/L neomycin, 1 g/L ampicillin, 1 g/L cefoperazone, and 0.5 g/L vancomycin) was administered for 8 days via drinking water to ablate the commensal gut microbiome prior to fecal microbiota transplantation (FMT). Following 2 FMT gavages (FMT A and B), E0771 breast cancer cells were injected into the fourth right mammary fat pad and monitored for 3 weeks. Two additional FMT gavages occurred following cell injection (FMT C and D). αPD-1 immune checkpoint blockade (ICB) therapy or IgG2a isotype control was administered at 200 μg/mouse intraperitoneally every 3 days from tumor injection to endpoint. Additional controls not depicted in the cartoon are reported in Supplemental Figure 1. (B) Tumor progression was recorded by digital caliper and quantified until endpoint. n = 8–10 per group. (C) Tumor volume at endpoint presented as mean ± SEM with comparisons determined by 2-way ANOVA. n = 8–10 per group. (D) Semisupervised heatmap of RNA-seq transcriptomic analysis of tumors from mice receiving Obese or VSG FMT and αPD-1 ICB or IgG2a isotype control. Top 50% of differentially expressed genes are shown. n = 3–6 per group. (E) Dot plots of gene set enrichment analysis (GSEA) results representing upregulated and downregulated HALLMARK pathways in VSG FMT recipients plotted as αPD-1 ICB versus IgG2a isotype control, with significant nominal P values denoted by dot color and gene count signified by dot size. Pathways are ranked by normalized enrichment score (NES). (F and G) Volcano plots of significant differentially expressed genes in tumors from Obese FMT (F) and VSG FMT (G) recipients plotted as αPD-1 ICB versus IgG2a isotype control with log2 fold change (FC) of greater than 1.5 and adjusted P value of less than 0.05. n = 3–6 per group. *P < 0.05.