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。但是，它们在晚期乳腺癌中的效用受到限制。例如，免疫检查点阻滞剂（ICB）在复发或转移性乳腺癌中几乎没有效率，没有效率。高雌激素水平在乳腺肿瘤微环境（TME）中，可能会损害对ICB的反应，因为17β-雌二醇（E2），通过激活雌激素受体α（ERα/ESR1），激活免疫抑制髓样抑制细胞（MDSC）会损害对ICB的反应。越来越多的证据表明肠道微生物组，通过饮食修饰，在对ICB的反应中起着至关重要的作用。在我们的试点研究中，同种异体移植ESR1负的增长当小鼠也接受治疗时，抗PD1 ICB治疗可显着抑制E0771鼠乳腺肿瘤 ESR1抑制抗雌激素莫昔芬。但是，这种影响强烈依赖于喂食的饮食老鼠。仅在食用5058啮齿动物实验室饮食的小鼠中才能看到这种效果或AIN93G啮齿动物饮食。 5058和5v5m饮食之间的主要区别在于，只有5058个含有大豆在异黄酮染料木黄酮（Gen）中含量很高。 5v5m饮食含有低水平的异黄酮，AIN93G确实不包含任何gen。尽管Gen具有与E2相似的化学结构，但它优先结合其他雌激素受体：ERβ/ESR2。 ERβ与ERα的作用相反，其激活增强了免疫并抑制影响炎症，包括肠道。由于Gen修改了肠道微生物组，我们将在此处进行调查如果抗PD1+抗雌激素在促进消除乳腺肿瘤中的饮食依赖性作用。通过Gen对肠道微生物组的影响。这将通过从Gen Fed供体中移植粪便微生物组来完成小鼠对无菌接受者小鼠的小鼠，并确定接受的接受者小鼠是否保留在无基因饮食上作为抗PD1 + Fulvestort的抗小鼠也很好地喂养了gen。然后，我们将研究Gen对肠道微生物组的影响是否通过使用有条件的敲除小鼠，由Gen结合和激活肠道中的ERβ/ESR2介导在肠中不表达ESR2。最后，我们将比较gen与ESR2激动剂LY500307的效果，目前正在临床试验中，以修改对PD1阻塞和富雾剂的反应。如果我们显示了潜力补充Gen或Ly500307，以增加乳腺肿瘤对抗PD1治疗的反应能力通过抗雌激素治疗，这可能允许患有晚期疾病的乳腺癌患者利用功率免疫疗法。