Small extracellular vesicles as biomarkers of prognosis and response to therapy in head and neck cancer
小细胞外囊泡作为头颈癌预后和治疗反应的生物标志物
基本信息
- 批准号:10659374
- 负责人:
- 金额:$ 64.07万
- 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:2023-03-15 至 2027-12-31
- 项目状态:未结题
- 来源:
- 关键词:AftercareAntibodiesBiogenesisBiological AssayBiological MarkersBody FluidsCancer PatientCell SeparationCellsCharacteristicsClinicalCombined Modality TherapyDataDefectDevelopmentDiagnosisDiseaseDisease ProgressionEffector CellHPV-negative head and neck cancerHead and Neck CancerHead and Neck Squamous Cell CarcinomaHuman PapillomavirusImmuneImmune System DiseasesImmune checkpoint inhibitorImmunocompetenceImmunologicsImmunosuppressionImmunotherapyIndividualLeukocytesLigandsLinkMalignant NeoplasmsMediatingMetastatic/RecurrentMinorityMolecularMonoclonal AntibodiesMonoclonal Antibody TherapyMorbidity - disease rateNon-Invasive DetectionNon-MalignantOutcomeParentsPatient SelectionPatientsPerformancePhenotypePlasmaPlasma CellsPrediction of Response to TherapyPrognosisPrognostic MarkerProteinsQuality of lifeRegulatory T-LymphocyteReportingResistanceResolutionRoleSamplingSelection for TreatmentsT-LymphocyteTechnologyTestingToxic effectTumor-DerivedVesicleWestern Blottingadvanced diseaseaggressive therapyanti-PD-1cancer biomarkerscancer therapycarcinogenesisclinical developmentclinically relevantdisorder controlexosomeextracellular vesiclesimprovedimproved outcomeineffective therapiesmortalitynanoflow cytometryneoplastic cellnovelpatient prognosispatient subsetspembrolizumabpotential biomarkerpredictive markerprognosis biomarkerprogramsresponse biomarkerstandard carestandard of caretherapy resistanttreatment response
项目摘要
PROJECT SUMMARY/ABSTRACT
Biomarkers that reliably inform the selection of therapy or prognosis for patients with head and neck squamous
cell carcinoma (HNSCC) are lacking. This can result in the use of overly aggressive or ineffective therapy with
the associated negative impact on quality of life and mortality. Thus, there is a great need for the development
of non-invasive biomarkers that accurately predict response to therapy or prognosis of HNSCC. Emerging data
suggest that analysis of the cargos of small (30-150 nm) extracellular vesicles (sEV), also known as exosomes,
in body fluids is a promising approach to the detection of non-invasive biomarkers in cancer, including HNSCC.
In cancer patients, plasma sEV are mixtures of tumor-derived exosomes (TEX) and vesicles produced by non-
malignant cells (NTEX) such as leukocytes. We found that TEX are a prominent but variable subset of sEV in
HNSCC patients’ plasma. TEX recapitulate the content of tumor cells, while the molecular cargo of NTEX
resembles that of non-malignant leukocytes, largely T cells, reprogrammed by TEX. Our data indicate that both
these sEV subsets mediate immune suppression and influence responses to therapy. We hypothesize that in
HNSCC patients, TEX as well as NTEX mediate immune suppression and are responsible for poor prognosis
and resistance to anti-cancer therapies. Using a novel immune capture-based technology, we will separate TEX
from NTEX in HNSCC patients’ plasma and will then simultaneously evaluate these two sEV subsets as potential
biomarkers. In Aim 1, we will establish efficacy of the immune capture strategy for TEX and NTEX isolation from
HNSCC patients’ plasma and determine the potential of these sEV subsets to serve as biomarkers of cancer
and immune competence, respectively. Levels as well as phenotypic profiles and immunosuppressive functions
of the two sEV subsets will be evaluated and assessed for their ability to discriminate HNSCC patients from
healthy donors (HDs). In addition, high-resolution (HR) LC-MS/MS will be used to identify proteins in TEX and
NTEX that could be utilized as prognostic or predictive biomarkers. In Aim 2, we will evaluate the utility of TEX
and NTEX as biomarkers of prognosis in patients with locally advanced HNSCC treated with standard of care
therapy (N=200). Utilizing TEX and NTEX isolated from well-annotated existing pre-treatment plasma samples,
nanoflow cytometry, functional assays, and targeted HR LC-MS/MS will be used to assess phenotypic profiles
and immunosuppressive functions. We will correlate TEX and NTEX plasma levels and profiles with clinical
endpoints. In Aim 3, we will investigate the utility of TEX and NTEX as biomarkers of response to anti-PD-1 mAb
immunotherapy in HNSCC patients diagnosed with recurrent/metastatic disease (N=80). TEX and NTEX
characteristics will be assessed as in Aim 2, and we will evaluate whether they are predictive of the efficacy of
anti-PD-1 mAb therapy. The simultaneous assessment of TEX and NTEX in plasma of HNSCC patients will
confirm the role of these two sEV subsets as biomarkers of cancer as well as of cancer-induced defects in
immune competence. Importantly, these biomarkers, alone or together, have the potential to guide selections of
therapies that will improve outcome and reduce morbidity and mortality in patients with HNSCC.
项目摘要/摘要
为头颈部鳞状细胞癌患者的治疗选择或预后提供可靠信息的生物标志物
细胞癌(HNSCC)缺乏。这可能导致使用过度积极或无效的治疗,
对生活质量和死亡率的相关负面影响。因此,非常需要开发
准确预测HNSCC治疗反应或预后的非侵入性生物标志物。新出现的数据
表明对小(30-150 nm)细胞外囊泡(sEV),也称为外来体,
在体液中的检测是检测癌症(包括HNSCC)中的非侵入性生物标志物的有前景的方法。
在癌症患者中,血浆sEV是肿瘤来源的外泌体(TEX)和由非肿瘤细胞产生的囊泡的混合物。
恶性细胞(NTEX),如白细胞。我们发现TEX是sEV的一个突出但可变的子集,
HNSCC患者血浆。TEX概括了肿瘤细胞的含量,而NTEX的分子货物
类似于非恶性白细胞,主要是T细胞,被TEX重编程。我们的数据显示,
这些sEV亚群介导免疫抑制并影响对治疗的应答。我们假设,
HNSCC患者,TEX以及NTEX介导免疫抑制,并导致预后不良
以及对抗癌疗法的抵抗力。使用一种新的基于免疫捕获的技术,
来自HNSCC患者血浆中的NTEX,然后将同时评估这两个sEV子集作为潜在的
生物标志物。在目标1中,我们将确定免疫捕获策略对从大肠杆菌中分离TEX和NTEX的功效。
HNSCC患者的血浆中,并确定这些sEV子集作为癌症生物标志物的潜力
和免疫能力。水平以及表型特征和免疫抑制功能
将评价和评估两个sEV亚组中的两个sEV亚组区分HNSCC患者和
健康供体(HD)。此外,高分辨率(HR)LC-MS/MS将用于鉴定TEX中的蛋白质,
NTEX可用作预后或预测生物标志物。在目标2中,我们将评估TEX的效用
和NTEX作为接受标准治疗的局部晚期HNSCC患者的预后生物标志物
治疗(N=200)。利用从注释良好的现有预处理血浆样品中分离的TEX和NTEX,
纳米流式细胞术、功能测定和靶向HR LC-MS/MS将用于评估表型特征
和免疫抑制功能。我们将TEX和NTEX血浆水平和谱与临床
端点。在目标3中,我们将研究TEX和NTEX作为抗PD-1 mAb应答的生物标志物的效用
在诊断为复发性/转移性疾病的HNSCC患者中进行免疫治疗(N=80)。TEX和NTEX
将按照目标2评估这些特征,我们将评估它们是否可预测
抗PD-1 mAb治疗。HNSCC患者血浆中TEX和NTEX的同时评估将
证实了这两个sEV亚群作为癌症生物标志物以及癌症诱导的缺陷的作用,
免疫能力重要的是,这些生物标志物,单独或一起,有可能指导选择,
改善HNSCC患者的结局并降低发病率和死亡率的治疗。
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)
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Brenda B. Diergaarde其他文献
Brenda B. Diergaarde的其他文献
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{{ truncateString('Brenda B. Diergaarde', 18)}}的其他基金
Vitamin D3 Modulation of Inflammation and Lung Cancer Risk
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- 批准号:
8555304 - 财政年份:2001
- 资助金额:
$ 64.07万 - 项目类别:
Vitamin D3 Modulation of Inflammation and Lung Cancer Risk
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8567002 - 财政年份:
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