The gut microbiome enhances breast cancer immunotherapy following bariatric surgery

Bariatric surgery is associated with improved breast cancer (BC) outcomes, including greater immunotherapy effectiveness in a pre-clinical BC model. A potential mechanism of bariatric surgery-associated protection is through the gut microbiota. Here, we demonstrate the dependency of improved immunotherapy response on the post-bariatric surgery gut microbiome via fecal microbial transplant. Cecal contents were isolated from either obese controls that received sham surgery or formerly obese mice following bariatric surgery-induced weight loss and transferred by FMT to lean recipients. Response to aPD-1 immunotherapy was significantly improved following FMT from formerly obese bariatric-surgery treated mice. Microbes can impact tumor burden through microbially derived metabolites produced or modified by gut microbiota including branched chain amino acids (BCAA). Circulating BCAA correlated significantly with NK T cell content in the tumor microenvironment in both donor mice after bariatric surgery and in FMT recipients of donor cecal content after bariatric surgery compared to obese sham controls. Findings implicate a role of microbially-derived BCAA in activating anti-tumor immunity that is dependent upon bariatric surgery. Importantly, when stool from a patient who exhibited 25% weight loss post-bariatric surgery was transplanted into recipient mice and compared to the patient's pre-bariatric surgery stool transplant. Patient samples post bariatric surgery significantly reduced tumor burden by 2.4-fold and immunotherapy effectiveness was doubled. Taken together, findings suggest that reinvigorating anti-tumor immunity may be dependent upon microbially derived metabolites such as BCAA. Overall design: RNA -Seq data from bulk tumor (orthotopically injected with E0771 Mouse Triple Negative Breast Cancer Cells) in specific pathogen-free C57BL/6J mice, treated with obese fecal microbial transplant (with aPD-1 immune checkpoint blockade N = 4 or IgG2a isotype control N = 6) or vertical sleeve gastrectomy fecal microbial transplant (with aPD-1 immune checkpoint blockade N = 4 or IgG2a isotype control N = 5), grown for 17 days, excised, and snap frozen.