Response to immune checkpoint blockade improved in pre-clinical model of breast cancer after bariatric surgery.

ABSTRACT

Bariatric surgery is a sustainable weight loss approach, including vertical sleeve gastrectomy (VSG). Obesity exacerbates tumor growth, while diet-induced weight loss impairs progression. It remains unknown how bariatric surgery-induced weight loss impacts cancer progression or alters response to therapy. Using a pre-clinical model of obesity followed by VSG or diet-induced weight loss, breast cancer progression and immune checkpoint blockade therapy were investigated. Weight loss by VSG or weight-matched dietary intervention before tumor engraftment protected against obesity-exacerbated tumor progression. However, VSG was not as effective as diet in reducing tumor burden despite achieving similar weight and adiposity loss. Leptin did not associate with changes in tumor burden; however, circulating IL-6 was elevated in VSG mice. Uniquely, VSG tumors displayed elevated inflammation and immune checkpoint ligand PD-L1+ myeloid and non-immune cells. VSG tumors also had reduced T lymphocytes and markers of cytolysis, suggesting an ineffective anti-tumor microenvironment which prompted investigation of immune checkpoint blockade. While obese mice were resistant to immune checkpoint blockade, anti-PD-L1 potently impaired tumor progression after VSG through improved anti-tumor immunity. Thus, in formerly obese mice, surgical weight loss followed by immunotherapy reduced breast cancer burden. Finally, we compared transcriptomic changes in adipose tissue after bariatric surgery from patients and mouse models. A conserved bariatric surgery-associated weight loss signature (BSAS) was identified which significantly associated with decreased tumor volume. Findings demonstrate conserved impacts of obesity and bariatric surgery-induced weight loss pathways associated with breast cancer progression.

As the number of people classified as obese rises globally, so do obesity-related health risks. Studies show that people diagnosed with obesity have inflammation that contributes to tumor growth and their immune system is worse at detecting cancer cells. But weight loss is not currently used as a strategy for preventing or treating cancer. Surgical procedures for weight loss, also known as 'bariatric surgeries', are becoming increasingly popular. Recent studies have shown that individuals who lose weight after these treatments have a reduced risk of developing tumors. But how bariatric surgery directly impacts cancer progression has not been well studied does it slow tumor growth or boost the anti-tumor immune response? To answer these questions, Sipe et al. compared breast tumor growth in groups of laboratory mice that were obese due to being fed a high fat diet. The first group of mice lost weight after undergoing a bariatric surgery in which part of their stomach was removed. The second lost the same amount of weight but after receiving a restricted diet, and the third underwent a fake surgery and did not lose any weight. The experiments found that surgical weight loss cuts breast cancer tumor growth in half compared with obese mice. But mice who lost the same amount of weight through dietary restrictions had even less tumor growth than surgically treated mice. The surgically treated mice who lost weight had more inflammation than mice in the two other groups, and had increased amounts of proteins and cells that block the immune response to tumors. Giving the surgically treated mice a drug that enhances the immune system's ability to detect and destroy cancer cells reduced inflammation and helped shrink the mice's tumors. Finally, Sipe et al. identified 54 genes which were turned on or off after bariatric surgery in both mice and humans, 11 of which were linked with tumor size. These findings provide crucial new information about how bariatric surgery can impact cancer progression. Future studies could potentially use the conserved genes identified by Sipe et al. to develop new ways to stimulate the anti-cancer benefits of weight loss without surgery.