Rebalancing protein homeostasis enhances tumor antigen presentation
重新平衡蛋白质稳态增强肿瘤抗原呈递
基本信息
- 批准号:10478021
- 负责人:
- 金额:$ 2.33万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-09-11 至 2022-11-20
- 项目状态:已结题
- 来源:
- 关键词:AddressAdenocarcinoma CellAntigen PresentationAntigensAntitumor ResponseCell LineCell surfaceCellular immunotherapyDNADNA Sequence AlterationDoseEffector CellEpigenetic ProcessExhibitsExposure toGenesGenetically Engineered MouseGenomeHeat shock proteinsHumanImmuneImmune TargetingImmune systemImmunotherapyInterferon Type IILeadLiteratureLung AdenocarcinomaLung NeoplasmsMajor Histocompatibility ComplexMalignant - descriptorMalignant NeoplasmsMalignant neoplasm of lungMismatch RepairMolecular ChaperonesMolecular ConformationMusMutateMutationPathway interactionsPatientsPeptidesPharmacologyProteinsProteomeRelapseRoleSignal TransductionStressSurfaceT cell responseT-LymphocyteTestingTumor Antigensanti-tumor immune responsecancer celleffector T cellendoplasmic reticulum stressepigenomehuman diseaseimmune checkpoint blockadeimmunogenicitymouse modelmutantneoantigensneoplastic cellnovelnovel strategiesprotein foldingprotein misfoldingprotein phosphatase inhibitor-2proteostasisproteotoxicitysmall moleculesuccesstargeted treatmenttumortumor DNA
项目摘要
PROJECT SUMMARY / ABSTRACT
Cancers arise through a combination of genetic and epigenetic changes that facilitate their
immortality, but simultaneously create foreign antigens, which should render neoplastic cells detectable
by the immune system and target them for destruction. Despite the remarkable success of
immunotherapies targeting endogenous effector T-cells, many cancers still evade immune recognition.
A critical component of successful immunotherapy is robust antigen presentation through Major
Histocompatibility Complex Class I (MHC-I) [10, 15, 34]. Since antigens can be derived from the mutant
proteome present in cancers, it would be expected that tumor types with high mutational load, such as
lung adenocarcinoma (LUAD), are characterized by strong T cell responses. However, many patients
with these tumor types either fail to respond to immunotherapy, or relapse after initial treatment.
Inherent to malignant transformation is the induction of proteotoxic stress due to the accumulation
of mutated, conformationally aberrant proteins [5]. To overcome these stresses, cancer cells are
exquisitely dependent on molecular chaperones [28]. This phenomenon suggests that immunogenicity
generated by antigens derived from the aberrant genome and epigenome in cancer is dampened by the
function of chaperones and the protein folding machinery. Thus, I hypothesize that inducers of protein
misfolding stress lead to increased antigen presentation by MHC-I molecules and increased
immunogenicity.
I propose to explore the impact of destabilizing the mutant proteome of LUAD in order
to reveal it to the host’s immune system. The aims are as follows:
Aim 1: Analyze the impact of protein misfolding stress on antigen presentation by MHC-I
molecules. In this aim I will interrogate the impact of subtoxic doses of small molecule modulators of
protein folding on antigen presentation in human and murine LUAD cell lines. We expect to expose the
mutant proteome to the immune system without disrupting protein folding machineries essential
functions. Additionally, I will genetically and pharmacologically perturb the pathways involved in antigen
presentation, in order to understand the mechanisms by which modulators of proteotoxic stress amplify
and diversify antigen presentation in LUAD cell lines.
Aim 2: Analyze the role of HSP90i and other inducers of proteotoxic stress in a hyper-mutational
mouse model of lung adenocarcinoma (LUAD)
Low-dose treatment with modulators of cytoplasmic proteotoxic stress will be tested for their ability to
stimulate an anti-tumor response in a hyper-mutational mouse model of LUAD.
This proposal will highlight mechanistically novel strategies to drive anti-tumor immune responses.
项目摘要/摘要
癌症是通过基因和表观遗传变化的组合而产生的,这些变化促进了
永生,但同时产生外来抗原,这将使肿瘤细胞被检测到
通过免疫系统,并以它们为目标进行破坏。尽管取得了显著的成功,
针对内源性效应T细胞的免疫治疗,许多癌症仍然逃避免疫识别。
成功的免疫治疗的一个关键组成部分是通过主要的抗原提呈
组织相容性复合体I类(MHC-I)[10、15、34]。因为抗原可以从突变体中衍生出来
蛋白质组存在于癌症中,预计具有高突变负荷的肿瘤类型,如
肺腺癌(LUAD)的特点是T细胞反应强烈。然而,许多患者
这些类型的肿瘤要么对免疫治疗无效,要么在最初的治疗后复发。
恶性转化所固有的是由于积聚而诱导的蛋白毒性应激。
突变的、构象异常的蛋白质[5]。为了克服这些压力,癌细胞
精致地依赖分子伴侣[28]。这种现象表明,免疫原性
由来自癌症中异常基因组和表观基因组的抗原产生的
伴侣和蛋白质折叠机械的功能。因此,我假设蛋白质的诱导剂
错误折叠应激导致MHC-I分子抗原提呈增加,并增加
免疫原性。
我建议探索破坏LUAD突变蛋白质组稳定的影响
将其揭示给宿主的免疫系统。目标如下:
目的1:分析蛋白质错折叠应激对MHC-I抗原提呈的影响
分子。在这个目标中,我将询问亚毒性剂量的小分子调节剂对
蛋白质折叠对人和小鼠LUAD细胞系抗原提呈的影响。我们预计将揭露
突变蛋白质组在不破坏蛋白质折叠机制的情况下对免疫系统至关重要
功能。此外,我将从遗传学和药理学上扰乱与抗原有关的途径。
介绍,以了解蛋白毒素应激调节因子放大的机制
并使LUAD细胞系的抗原提呈多样化。
目的2:分析HSP90i和其他蛋白毒性应激诱导物在高度突变中的作用
小鼠肺腺癌模型(LUAD)
使用细胞质蛋白毒性应激调节剂的低剂量治疗将测试它们的能力
在LUAD高突变小鼠模型中激发抗肿瘤反应。
这项提议将突出机械上的新策略,以驱动抗肿瘤免疫反应。
项目成果
期刊论文数量(0)
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会议论文数量(0)
专利数量(0)
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Grissel Cervantes Jaramillo其他文献
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{{ truncateString('Grissel Cervantes Jaramillo', 18)}}的其他基金
Rebalancing protein homeostasis enhances tumor antigen presentation
重新平衡蛋白质稳态增强肿瘤抗原呈递
- 批准号:
10019317 - 财政年份:2019
- 资助金额:
$ 2.33万 - 项目类别:
Rebalancing protein homeostasis enhances tumor antigen presentation
重新平衡蛋白质稳态增强肿瘤抗原呈递
- 批准号:
9910728 - 财政年份:2019
- 资助金额:
$ 2.33万 - 项目类别:
Rebalancing protein homeostasis enhances tumor antigen presentation
重新平衡蛋白质稳态增强肿瘤抗原呈递
- 批准号:
10237321 - 财政年份:2019
- 资助金额:
$ 2.33万 - 项目类别:
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