Branched chain amino acids recruit NKT cells to enhance breast cancer response to ⍺PD-1 immune checkpoint blockade following bariatric surgery 3947

Abstract Description Bariatric surgery is associated with improved breast cancer outcomes, including greater immune checkpoint blockade (ICB) effectiveness. Here, we demonstrate the dependency of improved ICB response on the post-bariatric surgery gut microbiome via fecal microbial transplant (FMT). To test underlying mechanisms of post-surgery benefits on the microbiome, we utilized pooled cecal contents obtained from donor C57BL/6J mice who were either obese or formerly obese following bariatric surgery weight loss. Response to ICB was significantly improved following FMT with samples from bariatric surgery-treated mice. Remarkably, stool from a post-bariatric surgery patient was transplanted into recipient mice and showed potently improved ICB effectiveness compared to pre-surgery stool transplant. Post-surgery microbes doubled ICB response in both models. Microbes can impact tumor burden through microbially derived metabolites including branched chain amino acids (BCAA). Circulating BCAAs correlated significantly with natural killer (NK) T cell content in the tumor microenvironment (TME) in both donor mice after bariatric surgery and FMT recipients compared to obese sham controls. Supplementation of lean mice with BCAAs replicated improved ICB effectiveness and increased NKT cell content within the TME. Taken together, findings demonstrate an important role of the microbiome after bariatric surgery in boosting effectiveness of ICB that may be dependent upon BCAAs interacting with NKT cells. Funding Sources R01CA253329, U01CA272541, R37CA226969, R25CA203650, F32CA250192, The Obesity Society/Susan G. Komen Cancer Challenge Award 2018, R01DK127209, Tennessee Governor Pediatric Recruitment Grant, Tennessee Clinical and Translational Science Institute, UTHSC Alma and Hal Reagan Fellowship, UTHSC Summer Resesarch Scholarship, UTHSC Medical Summer Research Fellowship Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)