Reversing Tolerogenicity of Tumor Associated Dendritic Cells to Enhance Anti-Tumo

逆转肿瘤相关树突状细胞的耐受原性以增强抗肿瘤能力

• 批准号: 8725600
• 负责人: Stephanie Kaye Watkins
• 金额: $ 24.15万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-19 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8725600
• 关键词: Adoptive Transfer; Affect; Androgen Receptor; Androgens; Animals; Award; Binding Sites; Biochemical; Biopsy; CD8B1 gene; Cell Cycle Regulation; Cell physiology; Cells; Cessation of life; Collaborations; Complement; Complex; Data; Defect; Dendritic Cells; Estrogen Receptors; Estrogens; FOXO1A gene; FOXO3A gene; Female; Fertility; Future; Gender; Gene Targeting; Goals; Growth Factor; High Pressure Liquid Chromatography; Hormone Receptor; Hormones; Human; Immune; Immune Cell Activation; Immune Tolerance; Immune response; Immune system; Immunology; Immunotherapy; Infertility; Infiltration; Inflammatory Response; Investigation; Knowledge; Laboratories; Ligands; Ligation; Link; Lymphoid Tissue; Malignant Neoplasms; Malignant neoplasm of prostate; Mast Cell Neoplasm; Mediating; Melanoma Cell; Mentors; Methods; Modeling; Molecular; Mus; Mutation; NF-kappa B; Nuclear Translocation; Partner in relationship; Patients; Peripheral; Phase; Population; Positioning Attribute; Premature Ovarian Failure; Process; Promoter Regions; Prostate; Prostatic Neoplasms; Proteins; Publications; Regulation; Renal Cell Carcinoma; Reporting; Research; Research Personnel; Resources; Role; Scientist; Sex Bias; Sex Characteristics; Signal Transduction; T-Lymphocyte; Techniques; Technology; Testing; Time; Training; Tumor Antigens; Tumor Immunity; Tumor Suppressor Genes; Woman; Work; anticancer research; cancer therapy; cancer type; career; cytokine; falls; human disease; immunogenicity; interest; loss of function; male; mast cell; meetings; melanoma; men; neoplastic cell; novel; prevent; programs; response; success; symposium; trafficking; transcription factor; tumor; tumor growth; tumor microenvironment

It is well established that upon adoptive transfer of Ag specific CD8+ T cells into prostate tumor bearing (TRAMP) mice, the T cells become activated in the peripheral lymphoid tissues, a sub- population of these cells then traffic to the prostate and where they rapidly become tolerized. To study the mechanisms by which T cells become tolerized in the prostate, our research is focused on the interactions between tumor infiltrating T cells and tumor associated DCs (TADCs). Our recent publications in Cancer Research and The JCI along with our preliminary data herein show that prostate TADCs, but not normal prostate DCs, induce tolerance and suppressive activity in T cells. Furthermore, this induction of tolerance is regulated by DC and the expression of the FOXO3 protein. Importantly, these results were found to be translational to human disease. Tolerance induced by TADC isolated from human tumor biopsies was also found to be regulated by increased DC expression of FOXO3. Therefore, the proposed research will determine two critical mechanisms in FOXO3 expression and control of DC function; 1) the regulation of FOXO3 expression in DC by tumor produced factors and tumor infiltrating suppressive cells and 2) the mechanism through which FOXO3 induces tolerogenic function in DC. To achieve the proposed aims state of the art technology such as HPLC and mass spectometry will be used for the identification of proteins produced by tumors to induce FOXO3 expression and tolerogenic activity in DC. A second novel mechanism will be tested characterizing the interaction between DC and tumor infiltrating suppressive mast cells in maintaining suppressive DC in the tumor microenvironment. The mechanisms that regulate DC function particularly though FOXO3 interactions with proteins including, WNT/b-catenin, and androgen and estrogen receptors (AR & ER) will be extensively tested and characterized. Interestingly, our preliminary data demonstrate that there may be differential mechanisms by which FOXO3 induces tolerance in males and females. Silencing Foxo3 in female patients may have a detrimental effect as immune cells did not infiltrate tumors and tumors grew more rapidly in these mice. Therefore the influence of FOXO3 and signaling through the hormone axis will be tested. Several murine tumor models including prostate, melanoma and renal cell carcinomas will be used to test induction of FOXO3 regulated DC tolerance across difference types of cancer and animal work will be complemented by studies performed in DC isolated from human tumors. Completion of this study will provide new and novel specific targets in tumors and DC to enhance immune therapy. Furthermore, the characterization of the role of FOXO3 in controlling the activation of hormone receptors to regulate immune cell activation by gender associated mechanisms may be critical for determining immune therapies to be used for cancers in men and women. In addition to the scientific merit of this application, the candidate has proposed outstanding yet achievable career goals. In the short term the candidate attend classes to enhance understanding of molecular techniques, the process of acquiring an independent research position, transitioning to independence, and how to set up and manage a laboratory. She will continue to participate in seminars, and conferences to present data, continue to build upon her knowledge of immunology and establish networks of collaborators to assist in current and future studies. Additionally, a mutually agreed upon training plan and plan for transitioning to independence has been provided by both the candidate and mentor. For long term career goals the candidate has provided a clear step by step approach to successfully become an independent academic scientist. The receipt of this award will enhance both scientific aspects by furthering the research to identify potential targets to enhance immune therapy for cancer and for the advancement of the candidate's career by providing additional time and resources to attend classes and meetings that will assist in the building of collaborations and a successful research program. Specifically, the data generated during the R00 phase of the award will provide the groundwork for the candidate to apply for an R01 by the end of her second year as an independent investigator.

已经确定，在将Ag特异性CD 8 + T细胞过继转移到前列腺肿瘤中后， 携带TRAMP的小鼠，T细胞在外周淋巴组织中被激活， 然后这些细胞群运输到前列腺，并在那里迅速变得耐受。研究 T细胞在前列腺中变得耐受的机制，我们的研究集中在 肿瘤浸润性T细胞和肿瘤相关DC（TADC）之间的相互作用。我们最近 癌症研究和JCI沿着的出版物以及我们的初步数据表明，前列腺 TADC，而不是正常的前列腺DC，诱导T细胞的耐受性和抑制活性。 此外，这种耐受性的诱导受DC和FOXO 3蛋白的表达调节。 重要的是，发现这些结果可转化为人类疾病。耐受 从人肿瘤活检组织中分离的TADC也被发现受DC表达增加的调节。 FOXO3因此，拟议的研究将确定FOXO 3中的两个关键机制 DC功能的表达和控制; 1）肿瘤产生的DC中FOXO 3表达的调节 因子和肿瘤浸润抑制细胞和2）FOXO 3诱导的机制 DC中的致耐受性功能。 为了实现所提出的目标，最先进的技术，如HPLC和质谱法， 将用于鉴定由肿瘤产生的诱导FOXO 3表达的蛋白质， DC中的致耐受活性。第二个新的机制将进行测试，表征相互作用 DC和肿瘤浸润性抑制性肥大细胞之间在维持肿瘤中的抑制性DC中的作用 微环境调节DC功能的机制，特别是通过FOXO 3相互作用 与蛋白质，包括WNT/b-连环蛋白，雄激素和雌激素受体（AR & ER）将是 经过广泛测试和表征。有趣的是，我们的初步数据表明， FOXO 3诱导雄性和雌性耐受的不同机制。沉默Foxo 3基因 女性患者可能会产生有害影响，因为免疫细胞不会浸润肿瘤， 在这些老鼠身上更快。因此，FOXO 3和通过激素轴的信号传导的影响 会得到考验 包括前列腺癌、黑色素瘤和肾细胞癌在内的几种鼠肿瘤模型将在本文中进行描述。 用于测试在不同类型的癌症和动物中FOXO 3调节的DC耐受性的诱导 这项工作将通过在从人肿瘤中分离的DC中进行的研究来补充。完成本 该研究将为肿瘤和DC提供新的特异性靶点，以增强免疫治疗。 此外，FOXO 3在控制激素激活中的作用的表征 通过性别相关机制调节免疫细胞活化的受体可能对 确定用于男性和女性癌症的免疫疗法。 除了这项申请的科学价值外，候选人还提出了一项杰出的申请， 可实现的职业目标。在短期内，考生参加培训班，以提高对 分子技术，获得独立研究职位，过渡到 独立性，以及如何建立和管理实验室。她将继续参与 研讨会和会议，以提供数据，继续建立在她的免疫学知识， 建立合作者网络，以协助当前和未来的研究。此外，相互 双方都提供了商定的培训计划和向独立过渡的计划， 候选人和导师对于长期的职业目标，候选人已经提供了一个明确的步骤 成功成为一名独立学术科学家的方法。该奖项的获得将 通过进一步研究来加强科学方面，以确定潜在的目标， 癌症的免疫治疗，并通过提供额外的 时间和资源参加课程和会议，这将有助于建立合作和 成功的研究计划。具体而言，在授予的R 00阶段生成的数据将 为候选人在第二年年底前申请R 01提供基础， 独立调查员

项目成果

FOXO3, estrogen receptor alpha, and androgen receptor impact tumor growth rate and infiltration of dendritic cell subsets differentially between male and female mice.

FOXO3、雌激素受体 α 和雄激素受体对雄性和雌性小鼠的肿瘤生长速率和树突状细胞亚群浸润的影响存在差异。

• DOI: 10.1007/s00262-017-1972-4
• 发表时间: 2017
• 期刊: Cancer immunology, immunotherapy : CII
• 作者: Thompson,MatthewG;Peiffer,DanielS;Larson,Michelle;Navarro,Flor;Watkins,StephanieK
• 通讯作者: Watkins,StephanieK