Boosting Antitumor Immunity by Blocking Both Tumor and Adipose DDR1
通过阻断肿瘤和脂肪 DDR1 来增强抗肿瘤免疫力
基本信息
- 批准号:9980667
- 负责人:
- 金额:$ 47.69万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-05-05 至 2025-04-30
- 项目状态:未结题
- 来源:
- 关键词:AddressAdipocytesAdipose tissueAdoptive TransferAntitumor ResponseAttenuatedBindingBiological AssayBreast Cancer ModelBreast Cancer PatientCancer BiologyCell CompartmentationCell physiologyCellsClinicalClinical OncologyCoculture TechniquesCollagenCollagen FibrilCollagen ReceptorsCommunicationComplexDataDevelopmentDietExtracellular DomainFutureHumanImmuneImmunocompetentImmunologicsImmunooncologyImmunophenotypingImmunosuppressionImmunotherapeutic agentImmunotherapyIn VitroIn complete remissionInfiltrationIntegration Host FactorsKnock-outKnockout MiceKnowledgeLigandsLiteratureMammary NeoplasmsMediatingMolecularMusNew AgentsNon obeseObesityObesity associated cancerPatient-Focused OutcomesPatientsPhosphotransferasesPositioning AttributeProductionProtein Tyrosine KinaseReceptor Protein-Tyrosine KinasesReportingResistanceRoleSamplingSignal TransductionStromal NeoplasmTechnologyTestingTimeTissuesTumor ImmunityWomananti-tumor immune responseattenuationbasecancer immunotherapycell typecomorbiditycytokinediscoidin domain receptor 1experimental studyimmunoregulationmalignant breast neoplasmmigrationmouse geneticsmouse modelmultidisciplinaryneoplastic cellnovelpatient subsetsresponsetargeted treatmenttooltumortumor growthtumor immunologytumor microenvironmenttumor progression
项目摘要
ABSTRACT
Despite significant clinical breakthroughs in anticancer immunotherapy, the efficacy of current
immunotherapies in breast cancer is modest. Only a small fraction of breast cancer patients have a clinical
response; complete responses to these agents are exceedingly rare. The underlying mechanisms of tissue-
specific immune regulation in breast cancer remains to be elucidated. Furthermore, how comorbidities such as
obesity influence antitumor immunity in breast cancer is even less understood.
Discoidin domain receptor 1 (DDR1) is a collagen receptor with an intrinsic tyrosine kinase activity. High
DDR1 expression in breast cancer is associated with poor patient outcomes and attenuated antitumor
immunity. We found complex tumor-promoting actions for both tumor and adipose DDR1 in the breast tumor
microenvironment. Tumor DDR1 suppresses antitumor immunity, whereas adipose DDR1 is required for diet-
induced obesity, tumor-promoting cytokine production, and immune modulation. Our preliminary data further
indicate that the shed extracellular domain of DDR1 alone is sufficient for its functions in tumor and adipose
cells, which has not previously been reported. We therefore hypothesize that DDR1 in the breast tumor
microenvironment promotes tumor progression by dampening antitumor immunity, enabling adiposity, and
abetting immune-adipose cell-tumor crosstalk. We predict that blocking kinase-independent DDR1 signals can
boost antitumor immunity and response to anticancer immunotherapies, especially in patients with obesity. To
test this hypothesis, in this R01 application, we will determine how tumor DDR1 suppresses antitumor
immunity (Aim 1), how adipose DDR1 contributes to obesity-associated cancer progression (Aim 2), and how
DDR1 carries out its immune-suppressive functions independent of its kinase activity (Aim 3). With combined
expertise in cancer biology, tumor immunology, and clinical oncology, our multidisciplinary team is well
positioned to validate our novel hypothesis.
The fact that DDR1 has distinct functions in different cell compartments of the breast tumor
microenvironment underscores the complexity of tumor-stromal interactions. By investigating tumor and
adipose DDR1 in an integrative and comprehensive manner as proposed here, we will fill major gaps of
knowledge about tumor-initiated immune suppression and obesity-associated comorbid effects. Given the
adipocyte-rich tumor microenvironment in breast cancer and the growing numbers of patients with obesity and
breast cancer, our proposed studies address an unmet clinical need and promise to inform the development of
new strategies to enhance antitumor immunity for breast cancer patients, especially for those with obesity.
!
摘要
尽管在抗癌免疫疗法方面取得了重大的临床突破,但目前的免疫疗法的疗效仍不理想。
乳腺癌的免疫治疗是适度的。只有一小部分乳腺癌患者有临床症状。
反应;对这些药物的完全反应非常罕见。组织的潜在机制-
乳腺癌中的特异性免疫调节仍有待阐明。此外,如何合并症,如
肥胖对乳腺癌抗肿瘤免疫力的影响更不清楚。
盘状结构域受体1(DDR 1)是具有内在酪氨酸激酶活性的胶原受体。高
乳腺癌中DDR 1表达与患者预后差和抗肿瘤活性减弱相关
免疫力我们在乳腺肿瘤中发现了肿瘤和脂肪DDR 1的复杂促肿瘤作用。
微环境肿瘤DDR 1抑制抗肿瘤免疫,而脂肪DDR 1是饮食所必需的。
诱导的肥胖、肿瘤促进细胞因子产生和免疫调节。我们的初步数据进一步
表明单独的DDR 1的脱落胞外结构域足以发挥其在肿瘤和脂肪组织中的功能,
细胞,这是以前没有报道过的。因此,我们假设乳腺肿瘤中的DDR 1
微环境通过抑制抗肿瘤免疫,使肥胖,
诱发免疫-脂肪细胞-肿瘤串扰。我们预测,阻断激酶非依赖性DDR 1信号可以
增强抗肿瘤免疫力和对抗癌免疫疗法的反应,尤其是肥胖患者。到
为了验证这一假设,在R 01申请中,我们将确定肿瘤DDR 1如何抑制抗肿瘤活性,
免疫(目标1),脂肪DDR 1如何促进肥胖相关的癌症进展(目标2),以及如何
DDR 1执行其免疫抑制功能,而不依赖于其激酶活性(Aim 3)。具有组合
在癌症生物学,肿瘤免疫学和临床肿瘤学方面的专业知识,我们的多学科团队
来验证我们的新假设
DDR 1在乳腺肿瘤的不同细胞区室中具有不同的功能,
微环境强调了肿瘤-基质相互作用的复杂性。通过研究肿瘤和
脂肪DDR 1在这里提出的综合和全面的方式,我们将填补主要空白,
了解肿瘤引发的免疫抑制和肥胖相关的共病效应。鉴于
乳腺癌中富含脂肪细胞的肿瘤微环境以及越来越多的肥胖和
乳腺癌,我们提出的研究解决了一个未满足的临床需求,并承诺告知发展
增强乳腺癌患者抗肿瘤免疫力的新策略,尤其是肥胖患者。
!
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)
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Rong Li其他文献
Rong Li的其他文献
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{{ truncateString('Rong Li', 18)}}的其他基金
Supplement to Support Research Training in HDAC11 and Cancer
支持 HDAC11 和癌症研究培训的补充品
- 批准号:
10380397 - 财政年份:2020
- 资助金额:
$ 47.69万 - 项目类别:
Boosting Antitumor Immunity by Blocking Both Tumor and Adipose DDR1
通过阻断肿瘤和脂肪 DDR1 来增强抗肿瘤免疫力
- 批准号:
10395597 - 财政年份:2020
- 资助金额:
$ 47.69万 - 项目类别:
Boosting Antitumor Immunity by Blocking Both Tumor and Adipose DDR1
通过阻断肿瘤和脂肪 DDR1 来增强抗肿瘤免疫力
- 批准号:
10159224 - 财政年份:2020
- 资助金额:
$ 47.69万 - 项目类别:
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