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

• 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
• 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

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）和人乳腺癌（HCC）] 表皮生长因子受体2（HER 2）阴性乳腺癌是乳腺癌的侵袭性亚型 目前还没有被批准的靶向治疗。虽然标准化疗可以降低 疾病事件，新辅助化疗后残留TNBC的患者具有局部区域性高风险 尽管进行了手术切除和积极的术后放疗，但仍会复发。因此， 了解TNBC进展的机制，并确定新的治疗方法， 在标准治疗下病情有进展的病人是非常需要的。PD-L1过表达， TNBC，相对于正常乳腺组织和其他乳腺癌亚型。PD-L1表达异常 肿瘤是逃避宿主免疫系统消除的重要手段。程序的绑定 死亡配体1（PD-L1）与其受体，程序性细胞死亡蛋白1（PD-1）传递信号，抑制T- 细胞激活因此，已经探索了消除PD-1/PD-L1与治疗性抗体的相互作用 作为增强抗肿瘤免疫力的手段。尽管PD-L1在调节T细胞中的细胞外作用， 尽管PD-L1在癌症中的潜在细胞内功能已经得到了很好的研究， 未知令人惊讶的是，我们发现TNBC增殖需要PD-L1，并且PD-L1的一个子集定位于 在细胞核中，并与粘连蛋白相互作用，粘连蛋白是一种蛋白质复合物，对适当的染色体 细胞周期中的排列和分离。我们的初步数据表明，PD-L1直接调节 TNBC中的凝聚力功能。敲除PD-L1显著导致染色体分离不完全 抑制TNBC细胞增殖，而对正常细胞无影响。被检验的中心假设 PD-L1调节三阴性乳腺癌细胞周期和染色体稳定性 癌症（TNBC），并靶向PD-L1或通路（有丝分裂和 由PD-L1调节的粘附素（cohesin）具有治疗用途。我们建议在实验中检验这一中心假设。 以下具体目的：目的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可能调节凝聚力的确切机制来研究肿瘤细胞增殖。 目的2、研究PD-L1对细胞周期和有丝分裂的调控。目的3，评价PD-L1的抑制 细胞核功能对染色体分离、肿瘤生长和放化疗反应的影响 和动物模型。从整体上看，这项工作的顺利完成将使影响更加完整 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治疗，不仅 通过抑制有丝分裂增强癌症治疗，但也释放患者免疫系统的抗肿瘤活性， 系统