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 5

Branched chain amino acid supplementation mimics the effects of the post–bariatric surgery microbiome.

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Branched chain amino acid supplementation mimics the effects of the post...
(A) Study schema: Female C57BL/6J mice were purchased from The Jackson Laboratory at 4 weeks of age. On day –7, a branched chain amino acid (BCAA) cocktail (15 g/L leucine, 15 g/L isoleucine, and 15 g/L valine) was administered via drinking water for the duration of the study. Following 7 days of BCAA supplementation, E0771 BC cells were injected into the fourth right mammary fat pad and monitored for 3 weeks. αPD-1 ICB therapy or IgG2a isotype control was administered at 200 μg/mouse intraperitoneally every 3 days from tumor injection to endpoint. (B) E0771 tumor progression was recorded by digital caliper. n = 9–10 per group. (C) E0771 tumor volume at endpoint is presented as mean ± SEM with comparisons determined by 2-way ANOVA; n = 9–10 per group. (D and E) Flow cytometric analysis of E0771 tumor immune microenvironment (TIME) shown as NK cells out of total CD45+ immune cells (D, NK1.1+CD3–) and invariant NKT (iNKT) cells (E; CD3+, PBS57-loaded mouse CD1d tetramer+) out of total CD3+ cells. Mean ± SEM with 2-way ANOVA for n = 5–9 per group. (F) Percentage of iNKT cells out of total CD3+ cells within E0771 TIME were correlated with tumor volume at endpoint via linear regression analysis. R2 = 0.13, P = 0.046, n = 30. (G) 4T1 tumor progression in BALB/c mice was recorded by digital caliper. n = 5 per group. (H–K) Flow cytometric analysis of 4T1 TIME shown as iNKT cells (H, PBS57-loaded mouse CD1d tetramer+) out of total CD45+ cells, and CD69+ iNKT cells (I), IFN-γ+ iNKT cells (J), and TNF-α+ iNKT cells (K) out of total iNKT cells. Data presented as mean ± SEM with 2-way ANOVA for n = 5 per group. *P < 0.05; ***P < 0.001; ****P < 0.0001.