Engineered Nanoformulation for Immune-modulation in Cancer

用于癌症免疫调节的工程纳米制剂

基本信息

项目摘要

Expression of immune check point (ICP) molecules on tumor cells and the host immune cells, especially T-cells present in the tumor milieu, negatively impact the cancer treatment outcome resulting in inefficient tumor eradication. Data also exist showing chemo- and radio- therapy induce ICP proteins on tumor cells and thereby contributing to inactivation of tumor infiltrating T-cells, resulting in the inability to host a robust antitumor response and culminating in treatment failure, and disease recurrence. Hence, understanding how a cancer drug impacts ICP will lead to development of new therapeutic strategies that can circumvent ICP-mediated treatment failure. One such approach is to incorporate immune check point inhibitors (ICPi) which can rekindle T-cell response and enhance the efficacy of anticancer drugs. Studies from the PI's laboratory and others have demonstrated genetic and pharmacologic inhibition of the human antigen R (HuR), an mRNA-binding protein that is overexpressed in human cancer cells, results in growth inhibition, reduction in metastasis, and in increased animal survival. While these findings support advancing HuR-targeted therapy for clinical translation, the PI's lab has recently made a serendipitous discovery showing siRNA- mediated silencing of HuR using a lipid-based nanoparticle (HuR-NP) induced programmed death-ligand (PD-L)1 expression in lung cancer cells. PD-L1 is one among several ICP proteins which when expressed by tumor cells suppress T-cell function. HuR-NP markedly induced PD- L1 mRNA and protein expression in human lung cancer cell lines. Molecular studies showed HuR binding site in the promoter region of PD-L1. Finally, a negative correlation between HuR and PD-L1 expression was observed in human lung cancer tissues. To our knowledge, apart from our own observation reported herein, there are no prior reports demonstrating the ability of HuR to regulate PD-L1 and testing of HuR-nanotherapy with PD-L1 immunotherapy for cancer. On the basis of our novel findings, we posit that combining HuR-nanotherapy with PD-L1 immunotherapy will demonstrate superior anticancer efficacy by eliciting strong immune response, and reducing disease recurrence. We will test our hypothesis with three aims: Aim 1. Determine the therapeutic benefit of LNP targeting HuR in combination with anti-PD-L1 therapy in vitro. Aim 2. Demonstrate LNP targeted HuR treatment in combination with PD-L1 immunotherapy in in vivo using lung tumor models elicits immune response and enhanced antitumor activity. Aim 3. Investigate the molecular mechanism by which LNP targeting HuR modulates PD-L1 expression in lung cancer cells.
免疫检查点(ICP)分子在肿瘤细胞和宿主免疫上的表达

项目成果

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Rajagopal Ramesh其他文献

Rajagopal Ramesh的其他文献

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{{ truncateString('Rajagopal Ramesh', 18)}}的其他基金

Exosomes as carriers of cancer therapeutics
外泌体作为癌症治疗的载体
  • 批准号:
    10312645
  • 财政年份:
    2021
  • 资助金额:
    $ 54.31万
  • 项目类别:
ShEEP Request for CytoViva 3D Darkfield Hyperspectral Microscope
ShEEP 请求 CytoViva 3D 暗场高光谱显微镜
  • 批准号:
    9906462
  • 财政年份:
    2019
  • 资助金额:
    $ 54.31万
  • 项目类别:
An improved IL-24 gene-based therapeutic for cancer
改进的基于 IL-24 基因的癌症疗法
  • 批准号:
    10326352
  • 财政年份:
    2019
  • 资助金额:
    $ 54.31万
  • 项目类别:
An improved IL-24 gene-based therapeutic for cancer
改进的基于 IL-24 基因的癌症疗法
  • 批准号:
    10544003
  • 财政年份:
    2019
  • 资助金额:
    $ 54.31万
  • 项目类别:
Cancer Research Training and Education Coordination
癌症研究培训和教育协调
  • 批准号:
    10627028
  • 财政年份:
    2018
  • 资助金额:
    $ 54.31万
  • 项目类别:
Molecular Impact of Platinum Drugs on the Proteasome and SQSTM1_P62 Complexes_A Paradigm Shift in Resistance
铂类药物对蛋白酶体和 SQSTM1_P62 复合物的分子影响_耐药范式转变
  • 批准号:
    10051382
  • 财政年份:
    2017
  • 资助金额:
    $ 54.31万
  • 项目类别:
Molecular Impact of Platinum Drugs on the Proteasome and SQSTM1_P62 Complexes_A Paradigm Shift in Resistance
铂类药物对蛋白酶体和 SQSTM1_P62 复合物的分子影响_耐药范式转变
  • 批准号:
    9478535
  • 财政年份:
    2017
  • 资助金额:
    $ 54.31万
  • 项目类别:
HuR Targeted Nanotherapy for Lung Cancer
HuR 靶向纳米疗法治疗肺癌
  • 批准号:
    8601528
  • 财政年份:
    2013
  • 资助金额:
    $ 54.31万
  • 项目类别:
HuR Targeted Nanotherapy for Lung Cancer
HuR 靶向纳米疗法治疗肺癌
  • 批准号:
    8785610
  • 财政年份:
    2013
  • 资助金额:
    $ 54.31万
  • 项目类别:
HuR Targeted Nanotherapy for Lung Cancer
HuR 靶向纳米疗法治疗肺癌
  • 批准号:
    8440451
  • 财政年份:
    2013
  • 资助金额:
    $ 54.31万
  • 项目类别:

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