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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取得了显著的成功。然而，它们在晚期乳腺癌中的应用一直是有限的。例如，免疫检查点阻滞剂 (ICBS)在复发或转移性乳腺癌的单一治疗中显示出很少或没有疗效。高雌激素水平在乳腺肿瘤微环境中，17β-雌二醇(E_2)可能通过激活雌激素受体α(ERα/ESR1)激活免疫抑制的髓系来源抑制细胞 (MDSCs)，这损害了对ICBS的反应。也有越来越多的证据表明，肠道微生物群，经饮食修饰后，在ICB的反应中起着关键作用。在我们的初步研究中，同种异体移植的ESR1生长为阴性抗PD1 ICB治疗对E0771小鼠乳腺肿瘤有显著抑制作用用ESR1抑制抗雌激素他莫昔芬。然而，这种效果很大程度上依赖于喂食的饮食老鼠。这种影响只在食用5058只啮齿动物实验饲料的小鼠身上看到，而在喂食5V5M的小鼠身上看不到或AIN93G啮齿动物饮食。5058和5V5M饮食的关键区别是只有5058含有大豆富含异黄酮染料木素(GEN)。5V5M饮食含有低水平的异黄酮类，AIN93G含有不包含任何基因。尽管Gen的化学结构类似于E2，但它优先与其他雌激素受体：ERβ/ESR2。ERβ与ERα相反的作用及其激活增强免疫力并抑制炎症，包括肠道内的炎症。由于Gen修改了肠道微生物组，我们将在这里进行调查抗PD1+抗雌激素促进乳腺肿瘤消除的饮食依赖效应是否存在通过基因对肠道微生物群的影响。这将通过移植Gen Feed捐赠者的粪便微生物群来完成小鼠与无菌受体小鼠之间的差异，并确定保持无基因饮食的受体小鼠是否会做出同样的反应抗PD1+Fulvestrant的效果很好，因为小鼠也喂食Gen。然后我们将研究Gen对肠道微生物群的影响是通过基因结合和激活肠道中的ERβ/esr2介导的，使用条件基因敲除小鼠进行肠道不表达ESR2。最后，我们将比较GEN和ESR2激动剂LY500307的作用。目前正在进行临床试验，以改变对PD1阻断和福尔维斯特的反应。如果我们展示出潜在的补充GEN或LY500307提高乳腺肿瘤对抗PD1治疗的反应性通过抗雌激素治疗，这可能使患有晚期疾病的乳腺癌患者能够利用这种力量免疫疗法。