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

Abstract

Bariatric surgery is becoming more prevalent as a sustainable weight loss approach, with vertical sleeve gastrectomy (VSG) being the first line of surgical intervention. We and others have shown that obesity exacerbates tumor growth while diet-induced weight loss impairs obesity-driven progression. It remains unknown how bariatric surgery-induced weight loss impacts cancer progression or alters responses to therapy. Using a pre-clinical model of diet induced obesity followed by VSG or diet-induced weight loss, breast cancer progression and immune checkpoint blockade therapy was investigated. Weight loss by bariatric surgery or weight matched dietary intervention before tumor engraftment protected against obesity-exacerbated tumor progression. However, VSG was not as effective as dietary intervention in reducing tumor burden despite achieving a similar extent of weight and adiposity loss. Circulating leptin did not associate with changes in tumor burden, however circulating IL-6 was elevated in mice after VSG. Uniquely, tumors in mice that received VSG displayed elevated inflammation and immune checkpoint ligand PD-L1+ myeloid and non-immune cells. Further, mice that received VSG had reduced tumor T lymphocytes and markers of cytolysis suggesting an ineffective anti-tumor microenvironment. VSG-associated elevation of PD-L1 prompted us to next investigate the efficacy of immune checkpoint blockade in lean, obese, and formerly obese mice that lost weight by VSG or weight matched controls. 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. Last, we compared transcriptomic changes in adipose tissue after bariatric surgery from both patients and mouse models that revealed a conserved bariatric surgery associated weight loss signature (BSAS). Importantly, BSAS significantly associated with decreased tumor volume. Our findings demonstrate conserved impacts of obesity and bariatric surgery-induced weight loss pathways associated with breast cancer progression.

The role of obesity and bariatric surgery-induced weight loss in breast cancer

“…VSG on rats is easier simply due to the large size of the animal, but bariatric surgery on female mice has also been conducted. We have reported in C57BL/6 J female mice, that DIO induced significant weight gain, increased adiposity, and leptin compared to lean low fat fed controls, which was lost in DIO mice after VSG [ 207 ]. In our study, we aimed to mimic epidemiologic findings of reduced breast cancer risk after bariatric surgery in patients discussed above.…”

“…Importantly, after weight loss by VSG, tumor progression was reduced. We showed that responsiveness to immune checkpoint blockade (ICB) immunotherapy was increased after VSG, but not in DIO mice, suggesting unique changes after bariatric surgery that primed for elevated efficacy of therapy [ 207 ]. In sum, despite limitations of extended time and costs using female mice to reach the extremes of obesity on a high fat diet compared to male mice, the use of female mice in DIO studies undergoing bariatric surgery is increasing.…”

“…However, this study was not a cancer immunotherapy study [ 306 ]. Indeed, published studies in murine models have not demonstrated elevated lethality in obese mice [ 207 , 307 ].…”

“…Obesity improves responsiveness to immunotherapy in melanoma and other cancers, but has not been reported for breast cancer [ 309 – 311 ]. One potential underlying mechanism is elevated inflammatory cytokines in obesity that stabilize PD-L1 or PD-1 [ 207 , 248 ]. Thus, inflammation associated with the obese tumor microenvironment may synergistically increase PD-L1 or PD-1.…”

“…We have begun to investigate the impact of VSG on breast cancer and immunotherapy. VSG itself induced PD-L1 which allowed for highly effective anti-PD-L1 immunotherapy in pre-clinical studies [ 207 ]. How obesity and weight loss, specifically by bariatric surgery, impacts the tumor microenvironment and systemic anti-tumor immunity, especially immune checkpoint ligands and immune cells, and response to ICB is under active investigation.…”