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Improving response to immunotherapy by genistein and antiestrogens

改善金雀异黄素和抗雌激素免疫疗法的反应

基本信息

批准号：
10112524
负责人：
LEENA A. HILAKIVI-CLARKE
金额：
$ 40.77万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-02 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10112524
关键词：
4T1 Affect Agonist Bacteria Binding Biological Breast Breast Cancer Patient C57BL/6 Mouse Carbohydrates Carcinogens Cells Chemical Structure Clinical Trials Consumption Diet ESR1 gene ESR2 gene Effectiveness Estradiol Estrogen Antagonists Estrogen Receptor alpha Estrogen Receptor beta Estrogen Receptors Estrogen receptor positive Estrogens Experimental Designs Fatty acid glycerol esters Fiber Fulvestrant Genistein Germ-Free Glioblastoma Growth Health Immune Immunity Immunomodulators Immunosuppression Immunotherapy Impairment Inflammation Intestines Isoflavones Knockout Mice Laboratories Link Malignant Neoplasms Mammary Neoplasms Mediating Metastatic breast cancer Modification Monoclonal Antibody Therapy Mus Myeloid-derived suppressor cells Neoplasm Metastasis Outcome PD-1/PD-L1 PDL1 inhibitors Pilot Projects Play Proteins Rattus Recurrence Reporting Rodent Role Signal Transduction Soybeans Supplementation TNFRSF1B gene Tamoxifen Translating Transplantation Tumor Immunity Up-Regulation advanced breast cancer advanced disease aggressive breast cancer anti-PD-1 anti-PD1 antibodies anti-PD1 therapy breast cancer progression cancer immunotherapy conditional knockout daidzein dietary dimethylbenzanthracene estrogenic fecal transplantation fight against gut dysbiosis gut microbiome immune checkpoint immune checkpoint blockers improved in vivo malignant breast neoplasm melanoma nano-string neoplastic cell preclinical study programmed cell death protein 1 response soy tumor tumor microenvironment

项目摘要

Cancer immunotherapies have been remarkably successful in treating many previously incurable cancers. However, their utility in advanced breast cancer has been limited. For example, immune checkpoint blockers (ICBs) show little to no efficacy as monotherapies in recurrent or metastatic breast cancer. High estrogen levels in the breast tumor microenvironment (TME) may impair the response to ICBs, as 17β-estradiol (E2), by activating estrogen receptor α (ERα/ESR1), activates immunosuppressive myeloid derived suppressor cells (MDSCs) which impair response to ICBs. There also is a growing evidence showing that the gut microbiome, modified by diet, plays a critical role in the response to ICB. In our pilot study, growth of allografted ESR1 negative E0771 murine mammary tumors was significantly inhibited by anti-PD1 ICB therapy when mice also were treated with ESR1 inhibiting antiestrogen tamoxifen. This effect, however, was strongly dependent on the diet fed to mice. The effect was seen only in mice which consumed 5058 rodent laboratory diet, but not in mice fed 5V5M or AIN93G rodent diet. The key difference between 5058 and 5V5M diets is that only 5058 contains soybeans which are high in isoflavone genistein (GEN). 5V5M diet contains low levels of isoflavones, and AIN93G does not contain any GEN. Although GEN has a chemical structure similar to that of E2, it preferentially binds to the other estrogen receptor: ERβ/ESR2. ERβ has opposite effects from ERα and its activation augments immunity and inhibits inflammation, including in the gut. Since GEN modifies the gut microbiome, we will investigate here if the diet-dependent effects of anti-PD1+antiestrogen in promoting elimination of mammary tumors are caused by GEN’s effect on the gut microbiome. This will be done by transplanting fecal microbiome from GEN fed donor mice to germ-free recipient mice, and determining if the recipient mice kept on GEN-free diet will respond equally well to anti-PD1 + fulvestrant as mice also fed GEN. We will then study if GEN’s effects on the gut microbiome are mediated by GEN binding and activating ERβ/ESR2 in the gut by using conditional knockout mice which do not express ESR2 in the intestine. Finally, we will compare the effects of GEN to that of ESR2 agonist LY500307, currently in clinical trials, in modifying response to PD1 blockage and fulvestrant. If we show the potential for supplementation with GEN or LY500307 to increase responsiveness of mammary tumors to anti-PD1 therapy with antiestrogen treatment, this might allow breast cancer patients with advanced disease to harness the power of immunotherapy.

癌症免疫疗法在治疗许多以前无法治愈的癌症方面非常成功。然而，它们在晚期乳腺癌中的效用有限。例如，免疫检查点阻断剂在复发性或转移性乳腺癌中，ICB作为单一疗法显示出很少或没有功效。高雌激素水平在乳腺肿瘤微环境（TME）中，可能通过以下方式损害对ICBs的反应，如17β-雌二醇（E2），激活雌激素受体α（ERα/ESR 1），激活免疫抑制性髓源性抑制细胞（MDSC），其损害对ICB的反应。还有越来越多的证据表明，肠道微生物组，通过饮食改变，在对ICB的反应中起关键作用。在我们的初步研究中，同种异体移植的ESR 1阴性 E0771小鼠乳腺肿瘤被抗PD 1 ICB治疗显著抑制，当小鼠也被治疗时与ESR 1抑制抗雌激素他莫昔芬。然而，这种效果强烈依赖于喂食的饮食，小鼠仅在食用5058啮齿动物实验室饮食的小鼠中观察到该效果，但在喂食5V5 M的小鼠中未观察到该效果或AIN 93 G啮齿动物饮食。5058和5V5 M日粮之间的关键区别在于，只有5058含有大豆其中高含量的染料木黄酮（GEN）。5V5 M饮食含有低水平的咖啡酮，而AIN 93 G含有虽然GEN具有与E2类似的化学结构，但它优先结合E2。其他雌激素受体：ERβ/ESR 2。ERβ具有与ERα相反的作用，其激活增强免疫并抑制炎症，包括肠道炎症由于GEN改变了肠道微生物组，我们将在这里进行研究。如果抗PD 1+抗雌激素在促进乳腺肿瘤消除方面的饮食依赖性作用 GEN对肠道微生物组的影响。这将通过移植来自GEN喂养供体的粪便微生物组来完成小鼠到无菌受体小鼠，并确定保持无GEN饮食的受体小鼠是否会同样响应我们将研究GEN对肠道微生物组的影响通过GEN结合和激活肠道中的ERβ/ESR 2介导，在肠道中不表达ESR 2。最后，我们将比较GEN与ESR 2激动剂LY 500307的作用，目前在临床试验中，用于改变对PD 1阻断和氟维司群的反应。如果我们展示出补充GEN或LY 500307以增加乳腺肿瘤对抗PD 1治疗的反应性通过抗雌激素治疗，这可能使晚期乳腺癌患者能够利用这种力量，免疫疗法。