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: 8529114
• 负责人: Stephanie Kaye Watkins
• 金额: $ 24.9万
• 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/8529114
• 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

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.

已经证实，在过继转移抗原特异性CD8+T细胞到前列腺肿瘤时 带着(TRAMP)小鼠，T细胞在外周淋巴组织中被激活，一种亚 这些细胞的数量然后流向前列腺，在那里它们很快就会被耐受。学习 T细胞在前列腺中的耐受机制，我们的研究重点是 肿瘤浸润性T细胞与肿瘤相关树突状细胞的相互作用我们最近 癌症研究和JCI上的出版物以及我们的初步数据显示，前列腺癌 TADCs，但不是正常的前列腺树突状细胞，能诱导T细胞的耐受和抑制活性。 此外，这种耐受性的诱导受DC和FOXO3蛋白表达的调节。 重要的是，这些结果被发现会转化为人类疾病。由以下因素引起的耐受 从人类肿瘤活检组织中分离出的TADC也被发现受到DC表达增加的调节 FOXO_3。因此，这项拟议的研究将确定FOXO_3的两个关键机制 DC功能的表达与调控：1)肿瘤对DC中FOXO_3表达的调节 因子与肿瘤浸润性抑制细胞2)FOXO_3诱导肿瘤侵袭的机制 DC的致耐受功能。 为了达到建议的目标，采用了最先进的技术，如高效液相色谱和质谱学 将用于鉴定肿瘤产生的诱导FOXO_3表达的蛋白质和 DC的耐受活性。第二种新的机制将被测试，以表征这种相互作用 DC与肿瘤浸润性肥大细胞在维持肿瘤内抑制性DC中的作用 微环境。调控DC功能的机制，特别是通过FOXO_3相互作用 有了包括WNT/b-连环蛋白在内的蛋白质，雄激素和雌激素受体(AR&ER)将 经过广泛的测试和表征。有趣的是，我们的初步数据显示， FOXO_3诱导男性和女性耐受的不同机制。让Foxo3安静下来 女性患者可能会有有害的影响，因为免疫细胞没有渗透到肿瘤中，肿瘤生长 在这些小鼠身上更快。因此FOXO_3的影响和通过激素轴的信号转导 将会受到考验。 包括前列腺癌、黑色素瘤和肾癌在内的几种小鼠肿瘤模型将被 用于在不同类型的癌症和动物中测试FOXO_3调节的DC耐受性的诱导 这项工作将得到在从人类肿瘤中分离的DC中进行的研究的补充。完成这项工作 这项研究将为肿瘤和DC提供新的、新的特异性靶点，以加强免疫治疗。 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激活的受体可能对 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，候选人还提出了杰出的 可实现的职业目标。在短期内，应聘者参加课程以增进对 分子技术，获得独立研究地位的过程，过渡到 独立性，以及如何建立和管理实验室。她将继续参加 提供数据的研讨会和会议继续建立在她的免疫学知识和 建立合作者网络，以协助当前和未来的研究。此外，一个相互的 商定的培训计划和向独立过渡的计划由双方提供 候选人和导师。对于长期的职业目标，候选人已经一步一步地提供了明确的 成功地成为一名独立的学术科学家。收到此奖项后， 通过进一步研究确定潜在的增强目标，加强这两个方面的科学研究 为癌症和候选人的职业发展提供更多的免疫治疗 有时间和资源参加有助于建立协作关系和 成功的研究项目。具体地说，在奖励的R00阶段生成的数据将 为候选人在第二年结束前申请R01奠定基础 独立调查员。