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:
  • 金额:
    $ 36.37万
  • 依托单位:
  • 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

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

项目成果

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Zhenkun Lou其他文献

Zhenkun Lou的其他文献

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{{ truncateString('Zhenkun Lou', 18)}}的其他基金

ATR: targeting mechanical stress induced EMT and immune suppression in triple negative breast cancer
ATR:针对三阴性乳腺癌中机械应力诱导的 EMT 和免疫抑制
  • 批准号:
    10658429
  • 财政年份:
    2023
  • 资助金额:
    $ 36.37万
  • 项目类别:
Sensitizing Ovarian Cancer To PARP inhibitor and platinum treatment
卵巢癌对 PARP 抑制剂和铂类治疗敏感
  • 批准号:
    10305524
  • 财政年份:
    2021
  • 资助金额:
    $ 36.37万
  • 项目类别:
Sensitizing Ovarian Cancer To PARP inhibitor and platinum treatment
卵巢癌对 PARP 抑制剂和铂类治疗敏感
  • 批准号:
    10415197
  • 财政年份:
    2021
  • 资助金额:
    $ 36.37万
  • 项目类别:
Sensitizing Ovarian Cancer To PARP inhibitor and platinum treatment
卵巢癌对 PARP 抑制剂和铂类治疗敏感
  • 批准号:
    10610944
  • 财政年份:
    2021
  • 资助金额:
    $ 36.37万
  • 项目类别:
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:
    10553119
  • 财政年份:
    2020
  • 资助金额:
    $ 36.37万
  • 项目类别:
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:
    10361225
  • 财政年份:
    2020
  • 资助金额:
    $ 36.37万
  • 项目类别:
Regulation of Necroptosis and inflammation
坏死性凋亡和炎症的调节
  • 批准号:
    10534748
  • 财政年份:
    2019
  • 资助金额:
    $ 36.37万
  • 项目类别:
Regulation of Necroptosis and inflammation
坏死性凋亡和炎症的调节
  • 批准号:
    10316176
  • 财政年份:
    2019
  • 资助金额:
    $ 36.37万
  • 项目类别:
UFM1 signaling in DNA damage response and cancer therapy
DNA 损伤反应和癌症治疗中的 UFM1 信号传导
  • 批准号:
    10304188
  • 财政年份:
    2017
  • 资助金额:
    $ 36.37万
  • 项目类别:
UFM1 signaling in DNA damage response and cancer therapy
DNA 损伤反应和癌症治疗中的 UFM1 信号传导
  • 批准号:
    10057359
  • 财政年份:
    2017
  • 资助金额:
    $ 36.37万
  • 项目类别:

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