Defining the effects of bortezomib on NK cell activation in cancer

确定硼替佐米对癌症 NK 细胞活化的影响

基本信息

  • 批准号:
    8475316
  • 负责人:
  • 金额:
    $ 36.38万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2013
  • 资助国家:
    美国
  • 起止时间:
    2013-07-12 至 2017-06-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Cancer remains the leading cause of death with a disproportionate toll on minority communities. Most common cancers are refractory to traditional treatments. With recent appreciation of cancer immunosurveillance mechanisms, our long-term objective is to elucidate immune mechanisms of cancer regression and to develop immunotherapy approaches that can specifically eliminate malignant cells and provide durable benefits in cancer patients. Recent studies in various pathophysiological models of immune rejection, including cancer, suggest an indispensable co-operativity in adaptive and innate immune effector cells. Our work in a mastocytoma model demonstrated that CD8+ T cells provided a necessary "help" to dormant natural killer (NK) cells in eliciting their antitumor function. This co-operativity of T cell and NK cell effector mechanisms led to complete tumor regression, by preventing the development of antigen-deficient tumor escape variants. A similar role of combined CD8+ T cells and NK cells was also observed by us in the rejection of mouse renal cell carcinoma Renca and by others in the control of mammary, bladder and intraperitoneal mesenchymal tumors. This signifies the importance of functional co-operativity of NK cells and T cells in tumor rejection. However, this protective team-work of T cells and NK cells fails in conditions of immunosuppressive chronic inflammation intrinsic to aggressive tumors as shown in inducible tumor models. Thus, it is imperative to investigate novel combinatorial therapeutic strategies and their mechanistic cross-talk to reduce tumor burden and potentiate anti-tumor immune effector functions by overriding tumor-induced immunosuppression. Based on our preliminary data, we hypothesize that combining tumor cell-death sensitizing bortezomib administration with adoptive NK cell transfer and immunostimulatory Notch activation should strengthen anti-tumor immune effector functions by modulating negative immune-regulatory circuits. This combinatorial strategy should overcome immunosuppressive effects of the chronic inflammation in tumor microenvironment and enhance therapeutic benefits against cancer. To test our hypothesis, we propose to address the following specific aims: Aim 1: Characterize the impact of bortezomib administration on tumor-infiltrating lymphoid and myeloid cells and their cytokine and chemokine production in the tumor microenvironment. Aim 2: Assess the effects of bortezomib on NK cell effector responses. Aim 3: Optimize NK cell adoptive therapy in combination with bortezomib and clustered multivalent DLL1 treatments in an established tumor. This proposal will be the first attempt at attacking the underexplored area of how anti-tumor functional co-operativity between the tumor- specific T cells and NK cells can be enhanced in the context of molecular targeting based on proteasome inhibition and immunostimulatory Notch signaling. The results will provide new insights for designing effective immunotherapy protocols relevant to cancers refractory to most conventional treatments and will have implications for pathophysiological conditions beyond cancer.
描述(由申请人提供):癌症仍然是主要的死亡原因,少数族裔社区的死亡人数不成比例。大多数常见的癌症对传统疗法是难以治愈的。随着对癌症免疫监测机制的最新认识,我们的长期目标是阐明癌症消退的免疫机制,并开发能够特异性地消除肿瘤细胞并为癌症患者提供持久益处的免疫治疗方法。最近对包括癌症在内的免疫排斥反应的各种病理生理学模型的研究表明,适应性免疫效应细胞和天然免疫效应细胞之间存在着不可或缺的协同作用。我们在肥大细胞瘤模型中的工作表明,CD8+T细胞为休眠的自然杀伤(NK)细胞在激发其抗肿瘤功能方面提供了必要的“帮助”。这种T细胞和NK细胞效应机制的协同作用,通过阻止抗原缺陷的肿瘤逃逸变异的发展,导致了肿瘤的完全消退。我们还观察到CD8+T细胞和NK细胞在小鼠肾细胞癌Renca的排斥反应中的作用,以及其他人在控制乳腺、膀胱和腹膜间充质肿瘤中的作用。这表明了NK细胞和T细胞在肿瘤排斥反应中功能协同作用的重要性。然而,这种T细胞和NK细胞的保护性团队工作在侵袭性肿瘤固有的免疫抑制慢性炎症条件下失败,如诱导性肿瘤模型所示。因此,迫切需要研究新的联合治疗策略及其机制串扰,以通过抑制肿瘤诱导的免疫抑制来减轻肿瘤负担并增强抗肿瘤免疫效应功能。根据我们的初步数据,我们推测,将肿瘤细胞死亡敏化的Bortezomib给药与过继的NK细胞转移和免疫刺激性Notch激活相结合,应该可以通过调节负免疫调节回路来增强抗肿瘤免疫效应功能。这一组合策略将克服肿瘤微环境中慢性炎症的免疫抑制效应,提高对癌症的治疗效果。为了验证我们的假设,我们建议解决以下具体目标:目标1:表征给药对肿瘤浸润性淋巴细胞和髓系细胞的影响,以及它们在肿瘤微环境中产生的细胞因子和趋化因子。目的2:评价硼替佐米对NK细胞效应的影响。目的3:在已建立的肿瘤中,优化NK细胞过继治疗联合Bortezomib和群集性多价DLL1治疗。这项提议将是第一次尝试攻击未被探索的领域,即如何在基于蛋白酶体抑制和免疫刺激Notch信号的分子靶向的背景下,增强肿瘤特异性T细胞和NK细胞之间的抗肿瘤功能合作。这一结果将为设计与大多数常规治疗难治的癌症相关的有效免疫治疗方案提供新的见解,并将对癌症以外的病理生理状况产生影响。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Anil Shanker其他文献

Anil Shanker的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Anil Shanker', 18)}}的其他基金

Diversity Center for Genome Research at Meharry
梅哈里基因组研究多样性中心
  • 批准号:
    10749781
  • 财政年份:
    2023
  • 资助金额:
    $ 36.38万
  • 项目类别:
Defining the effects of bortezomib on NK cell activation in cancer
确定硼替佐米对癌症 NK 细胞活化的影响
  • 批准号:
    9088384
  • 财政年份:
    2013
  • 资助金额:
    $ 36.38万
  • 项目类别:
Defining the effects of bortezomib on NK cell activation in cancer
确定硼替佐米对癌症 NK 细胞活化的影响
  • 批准号:
    8700356
  • 财政年份:
    2013
  • 资助金额:
    $ 36.38万
  • 项目类别:
Immunomodulatory effects of bortezomib on antitumor CD8 T-NK cell crosstalk
硼替佐米对抗肿瘤 CD8 T-NK 细胞串扰的免疫调节作用
  • 批准号:
    9770536
  • 财政年份:
    2013
  • 资助金额:
    $ 36.38万
  • 项目类别:
Pilot Project Developing immune checkpoint controlled -release biomaterials for cancer immunology
开发用于癌症免疫学的免疫检查点控释生物材料试点项目
  • 批准号:
    10493428
  • 财政年份:
    2011
  • 资助金额:
    $ 36.38万
  • 项目类别:
Pilot Project Developing immune checkpoint controlled -release biomaterials for cancer immunology
开发用于癌症免疫学的免疫检查点控释生物材料试点项目
  • 批准号:
    10327935
  • 财政年份:
    2011
  • 资助金额:
    $ 36.38万
  • 项目类别:
Defining immune footprint in tumor microenvironment following high salt synergized inflammatory cytokine mediated breast cancer progression
定义高盐协同炎症细胞因子介导的乳腺癌进展后肿瘤微环境中的免疫足迹
  • 批准号:
    10012769
  • 财政年份:
    2011
  • 资助金额:
    $ 36.38万
  • 项目类别:
Pilot Project Developing immune checkpoint controlled -release biomaterials for cancer immunology
开发用于癌症免疫学的免疫检查点控释生物材料试点项目
  • 批准号:
    10705096
  • 财政年份:
    2011
  • 资助金额:
    $ 36.38万
  • 项目类别:
Defining immune footprint in tumor microenvironment following high salt synergized inflammatory cytokine mediated breast cancer progression
定义高盐协同炎症细胞因子介导的乳腺癌进展后肿瘤微环境中的免疫足迹
  • 批准号:
    9765058
  • 财政年份:
  • 资助金额:
    $ 36.38万
  • 项目类别:
Defining immune footprint in tumor microenvironment following high salt synergized inflammatory cytokine mediated breast cancer progression
定义高盐协同炎症细胞因子介导的乳腺癌进展后肿瘤微环境中的免疫足迹
  • 批准号:
    9211644
  • 财政年份:
  • 资助金额:
    $ 36.38万
  • 项目类别:

相似海外基金

Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
  • 批准号:
    MR/S03398X/2
  • 财政年份:
    2024
  • 资助金额:
    $ 36.38万
  • 项目类别:
    Fellowship
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
  • 批准号:
    EP/Y001486/1
  • 财政年份:
    2024
  • 资助金额:
    $ 36.38万
  • 项目类别:
    Research Grant
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
  • 批准号:
    2338423
  • 财政年份:
    2024
  • 资助金额:
    $ 36.38万
  • 项目类别:
    Continuing Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
  • 批准号:
    MR/X03657X/1
  • 财政年份:
    2024
  • 资助金额:
    $ 36.38万
  • 项目类别:
    Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
  • 批准号:
    2348066
  • 财政年份:
    2024
  • 资助金额:
    $ 36.38万
  • 项目类别:
    Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
  • 批准号:
    AH/Z505481/1
  • 财政年份:
    2024
  • 资助金额:
    $ 36.38万
  • 项目类别:
    Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
  • 批准号:
    10107647
  • 财政年份:
    2024
  • 资助金额:
    $ 36.38万
  • 项目类别:
    EU-Funded
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
  • 批准号:
    2341402
  • 财政年份:
    2024
  • 资助金额:
    $ 36.38万
  • 项目类别:
    Standard Grant
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
  • 批准号:
    10106221
  • 财政年份:
    2024
  • 资助金额:
    $ 36.38万
  • 项目类别:
    EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
  • 批准号:
    AH/Z505341/1
  • 财政年份:
    2024
  • 资助金额:
    $ 36.38万
  • 项目类别:
    Research Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了