Targeting lymph node metastases to block cancer progression

针对淋巴结转移阻止癌症进展

基本信息

  • 批准号:
    10743193
  • 负责人:
  • 金额:
    $ 49.93万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-06-01 至 2028-05-31
  • 项目状态:
    未结题

项目摘要

Utilizing the power of lymph nodes to generate long-lasting, systemic anti-cancer immune responses has the potential to eradicate metastatic cancers from patients as seen with the recent success of immunotherapy in a subset of patients. The presence of lymph node metastases, however, brings with it a worse prognosis and the recommendation for systemic therapy for most cancer patients. Over the past 5+years our laboratory has shown that—beyond being a biomarker of the aggressiveness of the cancer—lymph node metastases play previously unrecognized roles in cancer progression, including by escaping the lymph node and seeding distant metastases. Our preliminary data also show that metastatic lymph nodes are immune suppressed, which leads to poor systemic anti-cancer immune responses and allows cancer progression. For patients with lymph node metastasis, immune suppression of lymph nodes needs to be overcome for successful immunotherapy. For the proposed work, we have generated strong preliminary data for two complementary mechanisms that we hypothesize cancer cells use in metastatic lymph nodes to drive immune suppression. First, our data show that a subset of cancer cells in metastatic lymph nodes express MHC class II molecules but not co-stimulatory molecules. We hypothesize that interactions of MHCII positive cancer cells with naïve lymphocytes will lead to CD4 T-cell suppression and Treg formation, limiting anti-cancer immune responses (Aim 1). We will determine the consequences of MHCII expression on cancer cells in metastatic lymph nodes for anti-cancer immune responses. Second, our data show limited lymphocyte infiltration into metastatic lesions in lymph nodes due to remodeling of high-endothelial venules. Further, we show that losartan treatment can induce lymphocyte infiltration into lymph node metastases. In the proposed work, we will determine the mechanism driving lymphocytic infiltration after losartan treatment and test the hypothesis that these infiltrated lymphocytes can be activated to promote anti-cancer immune responses (Aim 2). Finally, to generate an anti-cancer immune response against metastatic lymph node lesions, both lymphocytic activation (Aim 1) and infiltration (Aim 2) are required. Improving only one will likely not be sufficient to drive an anti-cancer immune response. Thus, we will test translational approaches to inhibit MHCII cancer cell expression to prevent suppression of lymphocytic immune response in combination with losartan to drive lymphocytic infiltration of metastatic lymph nodes (Aim 3). Our novel research program will discover critical mechanisms of immune suppression of metastatic lymph nodes as well as develop therapeutic strategies to overcome these mechanisms. To achieve these goals, we have assembled a world-class team of experts in lymph node metastasis (T. Padera), immunology (Mempel), cancer microenvironment (Jain), systems biology (Beyaz), pathology (R. Padera), clinical translation (Taghian) and biostatistics (Lee). The collective expertise and resources of the team will ensure successful completion of the proposed Aims and the exploration of novel treatment approaches for patients with metastatic cancer.
利用淋巴结的力量来产生持久的、系统性的抗癌免疫反应

项目成果

期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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TIMOTHY P PADERA其他文献

TIMOTHY P PADERA的其他文献

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{{ truncateString('TIMOTHY P PADERA', 18)}}的其他基金

Reversing aging-induced lymphatic dysfunction to improve immune function
逆转衰老引起的淋巴功能障碍,改善免疫功能
  • 批准号:
    10371505
  • 财政年份:
    2022
  • 资助金额:
    $ 49.93万
  • 项目类别:
Reversing aging-induced lymphatic dysfunction to improve immune function
逆转衰老引起的淋巴功能障碍,改善免疫功能
  • 批准号:
    10544735
  • 财政年份:
    2022
  • 资助金额:
    $ 49.93万
  • 项目类别:
2022 Lymphatics GRC and GRS
2022 淋巴 GRC 和 GRS
  • 批准号:
    10378787
  • 财政年份:
    2021
  • 资助金额:
    $ 49.93万
  • 项目类别:
Targeting lymph node metastases to prevent cancer progression
针对淋巴结转移预防癌症进展
  • 批准号:
    9286149
  • 财政年份:
    2017
  • 资助金额:
    $ 49.93万
  • 项目类别:
Targeting lymph node metastases to prevent cancer progression
针对淋巴结转移以预防癌症进展
  • 批准号:
    10542290
  • 财政年份:
    2017
  • 资助金额:
    $ 49.93万
  • 项目类别:
Characterization of lymphatic contraction during infection
感染期间淋巴收缩的特征
  • 批准号:
    8422972
  • 财政年份:
    2012
  • 资助金额:
    $ 49.93万
  • 项目类别:
Characterization of lymphatic contraction during infection
感染期间淋巴收缩的特征
  • 批准号:
    8225628
  • 财政年份:
    2012
  • 资助金额:
    $ 49.93万
  • 项目类别:
Characterizing lymphatic micrometastases: prognostic and therapeutic implications
淋巴微转移的特征:预后和治疗意义
  • 批准号:
    8146385
  • 财政年份:
    2011
  • 资助金额:
    $ 49.93万
  • 项目类别:
Lymphatic Radiobiology
淋巴放射生物学
  • 批准号:
    8326221
  • 财政年份:
    2008
  • 资助金额:
    $ 49.93万
  • 项目类别:
Lymphatic Radiobiology
淋巴放射生物学
  • 批准号:
    7686725
  • 财政年份:
    2008
  • 资助金额:
    $ 49.93万
  • 项目类别:

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