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 3

Microbes transplanted from VSG donors suggest elevated order Clostridiales in response to αPD-1 immune checkpoint blockade therapy.

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Microbes transplanted from VSG donors suggest elevated order Clostridial...
(A) Relative abundance of microbial families is reported from donor cecal contents harvested from obese sham or VSG donors at endpoint. Relative abundance was calculated using the top 1000 taxa identified using phyloseq (https://www.bioconductor.org/packages/release/bioc/html/phyloseq.html). n = 6–7 per group. (B) The α diversity in recipients across the timeline of the study included baseline stool collected on day –13, postantibiotic stool collected on day –5, and cecal contents taken at endpoint. Shannon and Simpson indices were calculated using phyloseq. n = 8–10 per group for VSG FMT recipients. Boxes represent the interquartile range (IQR) between the first and third quartiles, and the horizontal line inside the box defines the median. Whiskers represent the range of values from highest to lowest. Black dots inside the box represent the mean. (C) Relative abundance of microbial families is reported in recipient cecal contents harvested at FMT study endpoint. n = 8–10 per group. (D and E) Differential abundance analysis of endpoint cecal contents for family Peptostreptococcaceae (D) and order Clostridiales (E). Significant comparisons between relative abundance values were determined by 2-way ANOVA. n = 9–10 per group. *P < 0.05. (F) Abundance of order Clostridiales members in the cecal contents at endpoint were correlated with endpoint tumor volume via MaAsLin2 analysis. R2 = 0.12, P = 0.037, n = 38.