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 4

Elevated circulating branched chain amino acids were detected after FMT of VSG donor microbes, which correlated with improved antitumor immune response and NKT cells.

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Elevated circulating branched chain amino acids were detected after FMT ...
(A) Relative concentration of circulating branched chain amino acids (BCAAs, sum of valine, leucine, and isoleucine) quantified by GC-MS analysis of plasma. Data are presented as mean ± SEM with 2-way ANOVA comparisons for n = 9–10 per group. Black bars represent groups treated with IgG2a isotype control, while green bars represent groups treated with α-PD1 ICB. (B–D) Circulating individual BCAAs correlated with tumor volume at endpoint via linear regression analysis for valine (B; R2 = 0.12, P = 0.037, n = 36), leucine (C; R2 = 0.14, P = 0.022, n = 36), and isoleucine (D; R2 = 0.13, P = 0.034, n = 36). (E) Abundance of order Clostridiales members in cecal contents at endpoint were correlated with relative concentration of circulating BCAAs via MaAsLin2 analysis. R2 = 0.28, P = 0.029, n = 17. (F–J) Flow cytometric analysis of the tumor immune microenvironment (TIME) is shown as M1-like MHC IIhi macrophages (F; CD11b+Ly6C–Ly6G–F480+MHC IIhi), classical dendritic cells type 1 (G; cDC1s, CD11c+MHCII+CD11bloCD10hi), CD4+ memory T cells (H; CD4+CD44+CD69–), CD8+ memory T cells (I; CD8+CD44+CD69–), or NK/NKT cells (J, NK1.1+) out of total CD45+ immune cells. Data are presented as mean ± SEM with 2-way ANOVA comparisons for n = 6–9 per group. *P < 0.05; ***P < 0.001; ****P < 0.0001. (K) Percentage of NK/NKT cells out of total immune cells within the TIME were correlated with tumor volume at endpoint via linear regression analysis. R2 = 0.27, P = 0.002, n = 33. (L) Percentage of NK/NK T cells out of total immune cells within the TIME were correlated with circulating BCAA levels via linear regression analysis. R2 = 0.16, P = 0.034, n = 29.