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 6

Branched chain amino acid treatment increases iNKT cell production of proinflammatory cytokines.

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Branched chain amino acid treatment increases iNKT cell production of pr...
(A) Study schema: Liver lymphocytes were isolated from female C57BL/6J mice and FACS was used to isolate iNKT cells via PBS57-loaded mouse tetramer staining. Cells were expanded in culture for 20 days. On day 20, cells were treated with a branched chain amino acid (BCAA) cocktail (10 mM leucine, 10 mM isoleucine, and 10 mM valine) for 24 hours. On day 21, cells were stained for flow cytometric analysis. (B–D) Flow cytometric analysis of cultured cells at endpoint shown as iNKT cells (B, PBS57-loaded mouse tetramer+) out of total live cells, IFN-γ+ cells (C) and TNF-α+ cells (D) out of iNKT cells. Data presented as mean ± SEM with 2-tailed Student’s t test for n = 4 wells per group. *P < 0.05, **P < 0.01. (E) Proposed model: NKT cells are induced to mature by dendritic cells. Mature NKT cells activate antitumor immune cells including T cells and NK cells, which induce cancer cell death. Findings presented suggest that BCAAs are elevated in mice after FMT from VSG donors and are essential drivers of the NKT cell antitumor immune response. Solid lines indicate known interactions, while dashed lines represent proposed interactions.