Imaging tumor and T cell responses to metabolic and immune modulation therapy
成像肿瘤和 T 细胞对代谢和免疫调节治疗的反应
基本信息
- 批准号:10192675
- 负责人:
- 金额:$ 65.01万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-06-20 至 2022-09-15
- 项目状态:已结题
- 来源:
- 关键词:AdjuvantAffectAnimal Cancer ModelAnimalsBiological MarkersBreast Cancer PatientBreast Cancer TreatmentCD3 AntigensCD3E geneCD8-Positive T-LymphocytesCD8B1 geneCTLA4 geneCell SeparationCell physiologyCellsCellular Metabolic ProcessCharacteristicsClinicalClinical DataCombined Modality TherapyCytotoxic T-LymphocytesDataData SetDendritic CellsDiseaseExclusionFluorescenceGene ExpressionGene Expression ProfilingGenesGlycolysisGoalsHarvestHumanImageImaging TechniquesImmuneImmune checkpoint inhibitorImmunoPETImmunocompetentImmunofluorescence ImmunologicImmunohistochemistryImmunologic MonitoringImmunosuppressionImmunotherapyIn VitroInfiltrationInflammationLactate TransporterLactic acidLinkMCT-1 geneMagnetic Resonance ImagingMagnetic Resonance SpectroscopyMammary NeoplasmsMemorial Sloan-Kettering Cancer CenterMessenger RNAMetabolicMetabolismMetastatic breast cancerModelingMonitorMultimodal ImagingMusNatural Killer CellsNeoadjuvant TherapyNeoplasm MetastasisOperative Surgical ProceduresPD-1/PD-L1PatientsPenetrationPharmacologyPositioning AttributePositron-Emission TomographyPrediction of Response to TherapyProbabilityPrognosisPyruvateResistanceSolid NeoplasmT cell responseT-LymphocyteTherapeuticTreatment EffectivenessTreatment FailureTumor ImmunityTumor-infiltrating immune cellsaggressive breast canceranti-CTLA4anti-PD-1anti-PD-1/PD-L1basecancer imagingcell motilitycell typecellular imagingclinical translationclinically relevanteffectiveness evaluationextracellularimaging modalityimmune checkpointimmune checkpoint blockadeimmunogenicityimmunomodulatory therapiesimmunoregulationimprovedin vivoinhibitor/antagonistlactate dehydrogenase Amacrophagemalignant breast neoplasmmanmouse modelneoplastic cellnon-invasive imagingnoveloverexpressionprogrammed cell death protein 1responders and non-respondersresponsesuccesstherapeutic targettraffickingtreatment responsetreatment strategytriple-negative invasive breast carcinomatumortumor metabolismtumor microenvironmenttumorigenicuptake
项目摘要
PROJECT SUMMARY/ABSTRACT
Purpose of the project. This application focuses on the use of imaging to better understand, reverse, and
monitor immune suppression and metabolism in murine models of aggressive/metastatic breast cancer. High
LDH-A and monocarboxylate transporters 1 and 4 (MCT-1 and MCT-4) have been linked to poor prognosis,
and greater metastatic potential. Based on clinical analyses of GEO and MSKCC’s cBio Portal: i) tumors
with increased expression of genes involved in lactate metabolism are more aggressive and have poor
survival, and ii) there is an inverse correlation between the expression of glycolysis genes and immune-related
genes. These data support our hypothesis: that high rates of tumor glycolysis leads to a lactic acid-rich tumor
microenvironment (TME) with the exclusion of T cells, resulting in more aggressive tumors with a propensity to
form metastases. We further hypothesize that reversal of the T cell exclusion with metabolic inhibitors will
render tumors that are resistant to immune modulation with checkpoint blockade (CTLA-4, PD-1) to be
responsive to the treatment, due to repopulation of T cells within the tumor microenvironment.
Here, we propose to use multimodal imaging to explore the mechanisms by which metabolic and immune
modulation therapy reverse the restriction and inactivation of cytotoxic T cells in clinically relevant murine
models of aggressive breast cancer. We plan to: 1) characterize in vivo changes in tumor lactate and T cell
infiltration during LDH-A and MCT-1/4 inhibition; 2) evaluate the responses to adjuvant and neo-adjuvant single
and combination therapy (metabolic inhibition and “checkpoint” blockade in vivo); 3) validate the imaging
results by assessing correlations between glycolytic biomarkers and T cell infiltration using ex vivo
immunofluorescence (IF), immunohistochemistry (IHC), and fluorescence-assisted cell sorting (FACS); and 4)
assess the potential for clinical translation. The translational goal is two-fold: 1) to induce regression in primary
and metastatic breast cancer, by increasing tumor penetration and effector function of cytotoxic T cells, and 2)
to monitor treatment response by non-invasive imaging.
Experimental Strategy. We have established several murine models of aggressive breast cancer in immune
competent host animals. In Aim 1, in vitro and in vivo studies will define how tumor-cell metabolism affects T
cell function, and identify a “therapeutic window” for optimizing the magnitude and timing of T cell repopulation
of aggressive murine breast tumors following LDH and MCT pharmacologic inhibition. In Aim 2, metabolic and
immune-PET imaging will monitor how changes in the TME (induced by anti-LDH and anti-MCT treatment)
affect T cell infiltration and function. Based on Aim 1 and 2 studies, an “optimized” lactate inhibition treatment
strategy (established in Aims 1 and 2) will be combined with immune checkpoint blockade (anti-PD1 and anti-
CTLA4) and assessed in Aim 3. Imaging will be used to quantitate tumor lactate, the conversion of
hyperpolarized 13C-pyruvate to lactate, glycolysis (reflected in FDG uptake) and the trafficking of CD8+ T cells.
项目概要/摘要
项目的目的。该应用程序侧重于使用成像来更好地理解、反转和
监测侵袭性/转移性乳腺癌小鼠模型的免疫抑制和代谢。高的
LDH-A 和单羧酸转运蛋白 1 和 4(MCT-1 和 MCT-4)与预后不良有关,
和更大的转移潜力。基于 GEO 和 MSKCC cBio Portal 的临床分析: i) 肿瘤
随着乳酸代谢相关基因表达的增加,攻击性更强,且攻击性较差。
生存,ii) 糖酵解基因的表达与免疫相关基因之间存在负相关
基因。这些数据支持我们的假设:肿瘤糖酵解率高导致肿瘤富含乳酸
排除 T 细胞的微环境 (TME),导致更具侵袭性的肿瘤,并倾向于
形成转移。我们进一步假设,用代谢抑制剂逆转 T 细胞排斥将
使对检查点阻断(CTLA-4、PD-1)免疫调节有抵抗力的肿瘤成为
由于肿瘤微环境中 T 细胞的重新增殖,对治疗产生反应。
在这里,我们建议使用多模态成像来探索代谢和免疫的机制
调节疗法逆转临床相关小鼠细胞毒性 T 细胞的限制和失活
侵袭性乳腺癌模型。我们计划:1)表征肿瘤乳酸和 T 细胞的体内变化
LDH-A 和 MCT-1/4 抑制期间的浸润; 2) 评估对单一辅助剂和新辅助剂的反应
和联合治疗(代谢抑制和体内“检查点”阻断); 3) 验证成像
通过使用离体评估糖酵解生物标志物和 T 细胞浸润之间的相关性来获得结果
免疫荧光 (IF)、免疫组织化学 (IHC) 和荧光辅助细胞分选 (FACS);和 4)
评估临床转化的潜力。转化目标有两个:1)诱导初级回归
和转移性乳腺癌,通过增加肿瘤渗透和细胞毒性 T 细胞的效应功能,2)
通过非侵入性成像监测治疗反应。
实验策略。我们已经建立了几种侵袭性乳腺癌免疫小鼠模型
有能力的宿主动物。在目标 1 中,体外和体内研究将确定肿瘤细胞代谢如何影响 T
细胞功能,并确定优化 T 细胞再增殖的幅度和时间的“治疗窗口”
LDH 和 MCT 药理学抑制后侵袭性小鼠乳腺肿瘤的研究。在目标 2 中,代谢和
免疫 PET 成像将监测 TME 的变化(由抗 LDH 和抗 MCT 治疗引起)
影响T细胞浸润和功能。基于目标 1 和 2 研究,“优化的”乳酸抑制治疗
策略(在目标 1 和 2 中建立)将与免疫检查点封锁(抗 PD1 和抗
CTLA4)并在目标 3 中进行评估。成像将用于定量肿瘤乳酸,即
超极化 13C-丙酮酸为乳酸、糖酵解(反映在 FDG 摄取中)和 CD8+ T 细胞的运输。
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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JASON Arthur KOUTCHER其他文献
JASON Arthur KOUTCHER的其他文献
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{{ truncateString('JASON Arthur KOUTCHER', 18)}}的其他基金
Project 2: Early Detection of Breast Cancer Subtypes by Raman Spectroscopy with Heavy Water Labeling and MultiPhoton Microscopy
项目2:通过重水标记拉曼光谱和多光子显微镜早期检测乳腺癌亚型
- 批准号:
10250468 - 财政年份:2008
- 资助金额:
$ 65.01万 - 项目类别:
Project 2: Early Detection of Breast Cancer Subtypes by Raman Spectroscopy with Heavy Water Labeling and MultiPhoton Microscopy
项目2:通过重水标记拉曼光谱和多光子显微镜早期检测乳腺癌亚型
- 批准号:
10021578 - 财政年份:2008
- 资助金额:
$ 65.01万 - 项目类别:
Non-Invasive Markers of Tumor Response: A Study of Anti-Angiogenic Therapy
肿瘤反应的非侵入性标志物:抗血管生成治疗的研究
- 批准号:
7729463 - 财政年份:2008
- 资助金额:
$ 65.01万 - 项目类别:
Nuclear Magnetic Resonance Imaging of Tumor Hypoxia
肿瘤缺氧的核磁共振成像
- 批准号:
7102436 - 财政年份:2006
- 资助金额:
$ 65.01万 - 项目类别:
Optimizing Chemotherapy Dose Using 31P NMR Spectroscopy
使用 31P NMR 波谱优化化疗剂量
- 批准号:
7013706 - 财政年份:2005
- 资助金额:
$ 65.01万 - 项目类别:
Optimizing Chemotherapy Dose Using 31P NMR Spectroscopy
使用 31P NMR 波谱优化化疗剂量
- 批准号:
7140177 - 财政年份:2005
- 资助金额:
$ 65.01万 - 项目类别:
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