Response to immune checkpoint blockade improved in pre-clinical model of breast cancer after bariatric surgery.
Response to immune checkpoint blockade improved in pre-clinical model of breast cancer after bariatric surgery.
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DOI：
10.7554/elife.79143
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发表时间：
2022-07-01
期刊：
影响因子：
7.7
通讯作者：
Makowski, Liza
中科院分区：
文献类型：
--
作者：
Sipe, Laura M.;Chaib, Mehdi;Korba, Emily B.;Jo, Heejoon;Lovely, Mary Camille;Counts, Brittany R.;Tanveer, Ubaid;Holt, Jeremiah R.;Clements, Jared C.;John, Neena A.;Daria, Deidre;Marion, Tony N.;Bohm, Margaret S.;Sekhri, Radhika;Pingili, Ajeeth K.;Teng, Bin;Carson, James A.;Hayes, D. Neil;Davis, Matthew J.;Cook, Katherine L.;Pierre, Joseph F.;Makowski, Liza
关键词：
减肥手术是一种可持续的减肥方法，包括垂直袖状胃切除术（VSG）。肥胖会加剧肿瘤生长，而饮食引起的体重减轻会损害进展。目前尚不清楚减肥手术引起的体重减轻如何影响癌症进展或改变对治疗的反应。使用肥胖症的临床前模型，随后进行VSG或饮食诱导的体重减轻，研究了乳腺癌进展和免疫检查点阻断治疗。在肿瘤移植前通过VSG或体重匹配的饮食干预减轻体重可防止肥胖加重肿瘤进展。然而，VSG在降低肿瘤负荷方面不如饮食有效，尽管实现了相似的体重和肥胖减轻。瘦素与肿瘤负荷的变化无关;然而，VSG小鼠的循环IL-6升高。独特的是，VSG肿瘤显示炎症和免疫检查点配体PD-L1+骨髓和非免疫细胞升高。VSG肿瘤还具有减少的T淋巴细胞和细胞溶解标志物，表明无效的抗肿瘤微环境，这促使研究免疫检查点阻断。虽然肥胖小鼠对免疫检查点阻断具有抗性，但抗PD-L1通过改善抗肿瘤免疫力，在VSG后有效地损害肿瘤进展。因此，在以前肥胖的小鼠中，手术减肥后免疫治疗减少了乳腺癌负担。最后，我们比较了患者和小鼠模型的减肥手术后脂肪组织的转录组学变化。一个保守的减肥手术相关的体重减轻签名（BSAS）被确定为显着相关的肿瘤体积减小。研究结果表明，肥胖和减肥手术诱导的体重减轻途径与乳腺癌进展相关的保守影响。随着全球肥胖人数的增加，与肥胖相关的健康风险也在增加。研究表明，被诊断患有肥胖症的人有炎症，这有助于肿瘤的生长，他们的免疫系统在检测癌细胞方面更差。但减肥目前还没有被用作预防或治疗癌症的策略。外科手术减肥，也被称为“减肥手术”，正变得越来越受欢迎。最近的研究表明，在这些治疗后减肥的人患肿瘤的风险降低。但减肥手术如何直接影响癌症进展尚未得到充分研究：它是否会减缓肿瘤生长或增强抗肿瘤免疫反应？为了回答这些问题，Sipe等人比较了由于喂食高脂肪饮食而肥胖的实验室小鼠组的乳腺肿瘤生长。第一组小鼠在接受减肥手术后体重减轻，手术中部分胃被切除。第二个人减掉了同样多的体重，但接受了限制饮食，第三个人接受了假手术，没有减掉任何体重。实验发现，与肥胖小鼠相比，手术减肥可将乳腺癌肿瘤生长减少一半。但是，通过饮食限制减轻相同体重的小鼠比手术治疗的小鼠肿瘤生长更少。经过手术治疗的减肥小鼠比其他两组小鼠有更多的炎症，并且有更多的蛋白质和细胞阻止对肿瘤的免疫反应。给接受手术治疗的小鼠注射一种药物，可以增强免疫系统检测和摧毁癌细胞的能力，减少炎症，帮助缩小小鼠的肿瘤。最后，Sipe等人确定了54个基因，这些基因在小鼠和人类的减肥手术后被打开或关闭，其中11个与肿瘤大小有关。这些发现为减肥手术如何影响癌症进展提供了重要的新信息。未来的研究可能会使用Sipe等人发现的保守基因来开发新的方法来刺激无需手术减肥的抗癌益处。
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.