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The Interplay Between PD-1 Blockade and T cell Development in the Context of Thymic Regeneration in Prostate Cancer

前列腺癌胸腺再生背景下 PD-1 阻断与 T 细胞发育之间的相互作用

基本信息

批准号：
10370320
负责人：
Breanna Caruso
金额：
$ 4.68万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
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：
2021-06-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10370320
关键词：
Aftercare Animals Antigen-Presenting Cells Automobile Driving CD28 gene CRISPR/Cas technology Cancer Etiology Cancer Patient Castration Cell Count Cells Cellularity Cessation of life Clinical Treatment Clinical Trials Combined Modality Therapy Cytoplasmic Tail Data Dependence Development Diagnosis Generations Genomics Hormones Human Immune Immune checkpoint inhibitor Immunosuppression Immunotherapy Impact evaluation Inflammatory Response Lead Malignant Neoplasms Malignant neoplasm of prostate Mediator of activation protein Modeling Mus Mutate Outcome Output Pathway interactions Patients Peripheral Blood Mononuclear Cell Phenotype Play Population Process Prostate Prostate Cancer therapy Prostatic Neoplasms Proteomics Receptor Signaling Regulatory T-Lymphocyte Resistance Role Route Sampling Signal Pathway Signal Transduction Site Solid System T Cell Receptor Signaling Pathway T-Cell Development T-Cell Receptor T-Lymphocyte T-cell diversity Techniques Testing Therapeutic Thymic epithelial cell Thymus Gland Time Tumor Escape advanced prostate cancer androgen deprivation therapy anti-PD-1 anti-PD1 therapy anti-tumor immune response base immune checkpoint blockade in vivo men mouse model neoplastic cell progenitor programmed cell death ligand 1 programmed cell death protein 1 prostate cancer model resistance mechanism response screening standard of care therapy resistant thymic regeneration transcriptomics treatment response treatment strategy tumor tumor microenvironment tumor-immune system interactions

项目摘要

PROJECT SUMMARY Immunotherapies, such as PD-1 blockade, have shown therapeutic potential in prostate cancer; however, only a portion of patients respond, suggesting unidentified mechanisms of resistance. The current standard of care for prostate cancer is androgen deprivation therapy (ADT), which targets hormone-sensitive tumor cells. Interestingly, ADT also results in regeneration of the thymus and increased thymic output of newly developed T cells. We have shown that newly generated T cells resulting from ADT-induced thymic regeneration traffic to tumors where they can contribute to the tumor immune milieu. Further, PD-1 deficiency or blockade leads to an increase in the generation of thymic regulatory T cells (Tregs), suggesting that PD-1 regulates the selection of these cells in the thymus and, therefore, the Treg repertoire. It is unclear whether PD-1 limits Treg development by inhibiting the T cell receptor signaling pathway or the CD28 costimulatory pathway, but it has already been established that CD28 is critical for Treg development. Based upon these data, I hypothesize that inhibition of PD-1 could broaden the repertoire of Tregs available to traffic to prostate tumors and PD-1 limits Treg selection through inhibition of CD28 signaling. First, I will identify changes in tumor infiltrating Treg repertoire resulting from PD-1 blockade in the context of thymic regeneration. A castration model of ADT is used to induce thymic regeneration in a castration and immunotherapy resistant murine model of prostate cancer. Animals are treated with aPD-1 or control and the T cell repertoire is examined. Additionally, I will examine pre- and post- treatment samples collected as a part of an ongoing clinical trial where treatment-naïve men diagnosed with advanced prostate cancer receive ADT in combination with aPD-1, allowing us to perform real-time evaluation of the impact of PD-1 blockade during thymic regeneration on repertoire selection in patients . Second, I will determine the mechanism by which PD-1 limits Treg development. This will be accomplished through the use of the CRISPR-Cas9 system to mutate motifs in the CD28 cytoplasmic tail that are sites of PD-1 inhibition to determine dependence on CD28 signaling. Further, alterations of downstream signaling pathways resulting from PD-1 deficiency will be examined by transcriptomic and proteomic studies. The outcomes of this proposal are anticipated to reveal the how PD-1 blockade impacts the immune repertoire in the context of ADT-induced thymic regeneration to identify potential mechanisms of immunotherapy resistance in prostate cancer. These studies may also lead to new justifications for combination therapies in prostate cancer to increase the number of patients responding to checkpoint blockade.

项目摘要免疫疗法，如PD-1阻断，已显示出在前列腺癌中的治疗潜力;然而，一部分患者有反应，这表明了未确定的耐药机制。目前的护理标准前列腺癌的最佳治疗方法是雄激素剥夺疗法（ADT），其靶向是对雄激素敏感的肿瘤细胞。有趣的是，ADT还导致胸腺再生和新发育T细胞的胸腺输出增加。细胞我们已经证明，ADT诱导的胸腺再生所产生的新产生的T细胞可以通过运输到胸腺，它们可以促进肿瘤免疫环境。此外，PD-1缺陷或阻断导致PD-1缺乏。胸腺调节性T细胞（TCFs）的产生增加，表明PD-1调节胸腺调节性T细胞的选择。胸腺中的这些细胞，因此，Treg库。目前尚不清楚PD-1是否限制Treg的发育通过抑制T细胞受体信号通路或CD 28共刺激通路，但它已经被 CD 28对于Treg的发育至关重要。基于这些数据，我假设抑制 PD-1的表达可以拓宽可用于运输至前列腺肿瘤的Treg的库，并且PD-1限制了Treg 通过抑制CD 28信号传导进行选择。首先，我将确定肿瘤浸润性Treg库的变化，在胸腺再生的背景下由PD-1阻断引起。ADT的去势模型用于诱导前列腺癌去势和免疫治疗抗性小鼠模型中的胸腺再生。动物用aPD-1或对照处理，并检查T细胞库。此外，我将检查前和后- 作为正在进行的临床试验的一部分收集的治疗样本，在该临床试验中，晚期前列腺癌接受ADT联合aPD-1治疗，使我们能够进行实时评估，胸腺再生期间PD-1阻断对患者库选择的影响。第二，我会确定PD-1限制Treg发育的机制。这将通过使用 CRISPR-Cas9系统突变作为PD-1抑制位点的CD 28细胞质尾区中的基序，确定对CD 28信号传导的依赖性。此外，下游信号通路的改变导致的 PD-1缺陷将通过转录组学和蛋白质组学研究进行检查。该提案的结果是预计将揭示PD-1阻断如何在ADT诱导的胸腺免疫的背景下影响免疫库。再生，以确定前列腺癌中免疫疗法抗性的潜在机制。这些研究也可能导致前列腺癌联合治疗的新理由，以增加患者数量，对检查站封锁做出回应