The role of nuclear PD-L1 in breast tumor cell division, progression and therapy response

核PD-L1在乳腺肿瘤细胞分裂、进展和治疗反应中的作用

基本信息

批准号：
9897018
负责人：
Zhenkun Lou
金额：
$ 36.37万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9897018
关键词：
Acetylation Affect Animal Model Antibodies Attention Binding Breast Cancer Cell Breast Cancer Patient Cell Cycle Cell Cycle Regulation Cell Nucleus Cell Proliferation Cell division Chromosomal Stability Chromosome Segregation Chromosomes Clinical Combined Modality Therapy Data Disease Epidermal Growth Factor Receptor Estrogen Receptors Estrogen receptor positive Event Excision Genome Stability Human Immune Immune response Immune system In Vitro Malignant Neoplasms Mammary Gland Parenchyma Mitosis Neoadjuvant Therapy Normal Cell Nuclear Operative Surgical Procedures Pathogenesis Pathway interactions Patients Postoperative Period Progesterone Receptors Proteins Radiation therapy Recurrence Regulation Residual Tumors Residual state Risk Role Signal Transduction T cell regulation T cell response T-Cell Activation Testing Therapeutic Uses Therapeutic antibodies Tumor Immunity Variant Work Xenograft procedure breast cancer progression breast cancer survival cancer subtypes cancer therapy cell growth chemoradiation chemotherapy cohesin cohesion design extracellular glycosylation high risk knock-down malignant breast neoplasm mouse model neoplastic cell novel novel strategies overexpression programmed cell death ligand 1 programmed cell death protein 1 protein complex radiation response receptor response segregation standard care targeted treatment triple-negative invasive breast carcinoma tumor tumor growth

项目摘要

Triple negative breast cancer (TNBC) [estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) negative breast cancer is an aggressive subtype of breast cancer for which there are no approved targeted therapies. While standard chemotherapy reduces the risk of a disease event, patients with residual TNBC after neoadjuvant chemotherapy have a high risk of locoregional recurrence despite surgical resection and aggressive postoperative radiotherapy. Therefore, better understanding mechanisms of TNBC progression and identifying novel treatment approaches for patients who have progressed on standard treatment are of great needs. PD-L1 is overexpressed in TNBC, relative to normal breast tissue and other breast cancer subtypes. Aberrant PD-L1 expression on tumors is an important means of evading elimination by its host immune system. The binding of programmed death ligand 1 (PD-L1) to its receptor, programmed cell death protein 1 (PD-1) transmits signals that inhibit T- cell activation. Therefore, abrogating the PD-1/PD-L1 interaction with therapeutic antibodies has been explored as a means to enhance antitumor immunity. Although the extracellular role of PD-L1 in the regulation of T-cell responses has been well studied, potential intracellular functions of PD-L1 in cancer remain largely unknown. Surprisingly, we have found that TNBC proliferation requires PD-L1 and a subset of PD-L1 localizes in the nucleus and interacts with cohesin, a protein complex that is important for appropriate chromosome alignment and segregation during the cell cycle. Our Preliminary Data suggest that PD-L1 directly regulates cohesion function in TNBC. Knocking down PD-L1 dramatically causes incomplete chromosome segregation and inhibits TNBC cell proliferation, while has no effect on normal cells. The central hypothesis being tested in this proposal is that PD-L1 regulates cell cycle and chromosomal stability in triple negative breast cancer (TNBC), and targeting the intracellular/nuclear function of PD-L1 or pathways (mitosis and cohesin) regulated by PD-L1 is of therapeutic use. We propose to test this central hypothesis in the following Specific Aims: Aim 1, Determine the role of PD-L1 in regulation of cell cycle, genomic stability, and tumor cell proliferation by studying the exact mechanisms by which nuclear PD-L1 might regulate cohesion. Aim 2, Study the regulation of PD-L1 during cell cycle and mitosis. Aim 3, Evaluate the inhibition of PD-L1 nuclear function on chromosome segregation, tumor growth and response to radiochemotherapy both in vitro and in animal models. The overall impact from the successful completion of this work will be a more complete understanding of the role of PD-L1 in cancer pathogenesis. In addition, our work will lead to the design of more rational and effective combination therapies for TNBC patients by defining novel strategies that not only enhance cancer therapy by inhibiting mitosis but also unleash the antitumor activity of the patient’s immune system.

三阴性乳腺癌 (TNBC) [雌激素受体 (ER)、孕激素受体 (PR) 和人类表皮生长因子受体 2 (HER2) 阴性乳腺癌是一种侵袭性乳腺癌亚型目前还没有批准的靶向治疗方法，而标准化疗可以降低发生风险。疾病事件，新辅助化疗后残留 TNBC 的患者具有较高的局部区域风险尽管手术切除和积极的术后放疗仍会复发，因此效果更好。了解 TNBC 进展机制并确定新的治疗方法在标准治疗中取得进展的患者非常需要 PD-L1 过度表达。 TNBC，相对于正常乳腺组织和其他乳腺癌亚型的异常 PD-L1 表达。肿瘤是逃避其宿主免疫系统消除的重要手段。死亡配体 1 (PD-L1) 与其受体程序性细胞死亡蛋白 1 (PD-1) 传递抑制 T-的信号因此，人们正在探索消除 PD-1/PD-L1 与治疗性抗体的相互作用。尽管PD-L1在T细胞的调节中发挥细胞外作用。反应已得到充分研究，PD-L1 在癌症中的潜在细胞内功能在很大程度上仍然存在令人惊讶的是，我们发现 TNBC 增殖需要 PD-L1 和 PD-L1 的一个子集定位。在细胞核中并与粘连蛋白相互作用，粘连蛋白是一种对于适当染色体非常重要的蛋白质复合物我们的初步数据表明 PD-L1 直接调节细胞周期中的排列和分离。 TNBC 中的内聚功能显着降低 PD-L1 导致染色体分离不完全。并抑制 TNBC 细胞增殖，而对正常细胞没有影响正在测试的中心假设。该提案中的内容是 PD-L1 调节三阴性乳腺癌的细胞周期和染色体稳定性癌症 (TNBC)，并靶向 PD-L1 的细胞内/核功能或通路（有丝分裂和 PD-L1 调节的粘连蛋白）具有治疗用途，我们建议在以下方面测试这一中心假设。具体目标如下：目标 1，确定 PD-L1 在细胞周期调节、基因组稳定性和通过研究核 PD-L1 调节内聚力的确切机制，肿瘤细胞增殖。目标 2，研究 PD-L1 在细胞周期和有丝分裂过程中的调节作用。目标 3，评估 PD-L1 的抑制作用。体外核功能对染色体分离、肿瘤生长和放化疗反应的影响成功完成这项工作的总体影响将是更加完整。了解 PD-L1 在癌症发病机制中的作用此外，我们的工作将导致更多的设计。通过定义新策略，为 TNBC 患者提供合理有效的联合疗法，不仅通过抑制有丝分裂来增强癌症治疗，同时释放患者免疫系统的抗肿瘤活性系统。