Defining the role of innate immune cells in the early stages of immune surveillance of skin cancer by using a novel model that allows in vivo imaging of the immunoediting process.
通过使用允许对免疫编辑过程进行体内成像的新模型,定义先天免疫细胞在皮肤癌免疫监视早期阶段的作用。
基本信息
- 批准号:10704126
- 负责人:
- 金额:$ 50.87万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-15 至 2027-08-31
- 项目状态:未结题
- 来源:
- 关键词:AcademiaAddressBiopsyCellsChimeric ProteinsConfocal MicroscopyDataDevelopmentEarly DiagnosisEngineeringEpidermisEpitheliumEquilibriumEventGenerationsGenomicsGrowthHair RemovalHair follicle structureHumanImmuneImmune EvasionImmune systemImmunityImmunocompetentImmunologic MonitoringImmunologic SurveillanceImmunology procedureImmunosuppressionImmunotherapeutic agentImmunotherapyIn SituIndividualIndustryInterventionLesionLymphoid CellMaintenanceMalignant NeoplasmsMeasurableMediatingMesenchymalMethodsModelingMolecularMultiplexed Ion Beam ImagingMusNatural Killer CellsNeoplasmsNormal tissue morphologyPathway interactionsPatientsPharmaceutical PreparationsPhasePlayPreventionProcessProtein EngineeringResistance developmentResolutionRiskRoleSkinSkin CancerSystemTechniquesTestingTimeTissue ModelTransforming Growth Factor betaTransplantationTumor EscapeTumor ImmunityUp-RegulationVisualVisualizationWaxesanti-PD-L1cancer cellcancer immunotherapycancer preventioncancer therapycandidate identificationcandidate markercarcinogenesiscell transformationdifferential expressiondrug efficacydrug testingexperimental studyhigh riskimmunosuppressedin vivoin vivo imagingkeratinocytemouse modelneglectnon-invasive imagingnovelorgan transplant recipientpotential biomarkerpreventresistance mechanismscreeningtranscriptomicstumortumor growth
项目摘要
An understanding of cancer immune evasion has recently led to revolutionary immunotherapies and a
subsequent rush, by both industry and academia, to identify additional mechanisms of immune suppression
employed by cancer cells. Since these efforts rely on models of full-fledged cancer, there remains a neglected
opportunity to target neoplasms prior to the development of immune evasive character. The lack of models for
tracing de novo somatic transformation in vivo has prevented direct characterization of early carcinogenesis,
including the first interactions with immune cells. To address this deficiency, a novel mouse model has been
developed, which allows fluorescent tracing of individual transformed clones in the skin. A special transplant
technique has been used to integrate fluorescent, transformation-inducible keratinocytes into the epidermis of
an immunocompetent mouse, where they generate isolated, homeostatic clones. These colonies can be non-
invasively imaged at subcellular resolution via intravital confocal microscopy as transformation is induced. This
technique provides the first-ever direct visualization of cancer development in situ. Since immunity represents
a pivotal barrier to the successful outgrowth of neoplasms, this model was engineered to allow visualization of
immune cells, as well. The concept of immunoediting provides a framework for how cancers evolve immune-
evasive strategies during their development. Immunoediting includes a prolonged dormancy, termed the
“equilibrium phase”, during which immunity prevents tumor outgrowth without destroying the transformed cells.
For the first time, this model allows the observation of all three phases of immunoediting: elimination,
equilibrium, and escape, and reveals that the normal tissue microenvironment plays a central role in early
immune evasion. This novel model also reveals a role for innate immune cells in the early stages of immune
surveillance of skin cancer and in the maintenance of the equilibrium phase. During the equilibrium phase,
transformed cells may be uniquely sensitive to interventions since their lower numbers and relative
homogeneity will hinder development of resistance mechanisms. The ability to visualize de novo
transformation in this model allows this hypothesis to be tested. In addition, this model will allow the
characterization of mechanisms that mediate the hidden events of immunoediting. New preliminary data reveal
that the transition from equilibrium lesions to escape tumors involves the upregulation of TGFβ3 in escape
tumors, which concurrently undergo epithelial-mesenchymal transition. The increased levels of TGFβ3 convert
NK cells, that can inhibit tumor growth, into intermediate type 1 innate lymphoid cells that cannot inhibit tumor
growth. This revised application will further pursue both cellular and molecular mechanisms suggested by
these preliminary data. Finally, the ability to visualize immune-mediated dormant lesions may uncover potential
biomarkers, which might be translatable for early detection in high-risk human patients, such as
immunosuppressed organ transplant recipients, who have a 100-fold increased risk of developing skin cancer.
对癌症免疫逃避的理解最近导致了革命性的免疫疗法和免疫治疗。
随后,工业界和学术界都急于确定免疫抑制的其他机制,
被癌细胞利用。由于这些努力依赖于成熟癌症的模型,因此仍然存在一个被忽视的问题
在免疫逃避特性发展之前靶向肿瘤的机会。缺乏模型,
体内从头追踪体细胞转化阻止了早期癌发生的直接表征,
包括与免疫细胞的第一次相互作用。为了解决这一缺陷,一种新的小鼠模型已经被开发出来。
开发的,它允许在皮肤中的单个转化克隆的荧光示踪。一种特殊的移植
技术已被用于将荧光、转化诱导型角质形成细胞整合到表皮中,
免疫活性小鼠,在那里他们产生分离的,自我平衡的克隆。这些殖民地可以是非-
在诱导转化时,通过活体共聚焦显微镜以亚细胞分辨率侵入性成像。这
这项技术首次提供了原位癌症发展的直接可视化。既然豁免权代表着
肿瘤成功生长的关键障碍,该模型被设计为允许可视化
免疫细胞也是。免疫编辑的概念为癌症如何进化免疫提供了一个框架。
在发展过程中的策略。免疫编辑包括一种延长的休眠,称为免疫编辑。
“平衡期”,在此期间免疫防止肿瘤生长而不破坏转化的细胞。
该模型首次允许观察免疫编辑的所有三个阶段:消除,
平衡和逃逸,并揭示了正常组织微环境在早期
免疫逃避这种新的模型还揭示了先天免疫细胞在免疫早期阶段的作用。
监测皮肤癌和维持平衡阶段。在平衡阶段,
转化的细胞可能对干预特别敏感,因为它们的较低数量和相对较低的细胞毒性。
同质性将阻碍抗性机制的发展。重新想象的能力
在这个模型中的转换允许这个假设进行测试。此外,该模型将允许
表征介导免疫编辑的隐藏事件的机制。新的初步数据显示,
从平衡损伤到逃逸肿瘤的转变涉及逃逸过程中TGFβ3的上调,
肿瘤,其同时经历上皮-间充质转化。TGFβ3转化水平的增加
能够抑制肿瘤生长的NK细胞转化为不能抑制肿瘤生长的中间1型先天淋巴细胞
增长这一修订后的申请将进一步追求细胞和分子机制建议,
这些初步数据。最后,可视化免疫介导的休眠病变的能力可能会揭示潜在的
生物标志物,这可能是翻译为早期检测高风险的人类患者,如
免疫抑制的器官移植接受者,他们患皮肤癌的风险增加了100倍。
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 }}
Dennis Roop其他文献
Dennis Roop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('Dennis Roop', 18)}}的其他基金
Defining the role of innate immune cells in the early stages of immune surveillance of skin cancer by using a novel model that allows in vivo imaging of the immunoediting process.
通过使用允许对免疫编辑过程进行体内成像的新模型,定义先天免疫细胞在皮肤癌免疫监视早期阶段的作用。
- 批准号:
10522966 - 财政年份:2022
- 资助金额:
$ 50.87万 - 项目类别:
Testing the Therapeutic Potential of iPS Cells for Inherited Skin Diseases
测试 iPS 细胞对遗传性皮肤病的治疗潜力
- 批准号:
9516699 - 财政年份:2012
- 资助金额:
$ 50.87万 - 项目类别:
Testing the Therapeutic Potential of iPS Cells for Inherited Skin Diseases
测试 iPS 细胞对遗传性皮肤病的治疗潜力
- 批准号:
8707828 - 财政年份:2012
- 资助金额:
$ 50.87万 - 项目类别:
Testing the Therapeutic Potential of iPS Cells for Inherited Skin Diseases
测试 iPS 细胞对遗传性皮肤病的治疗潜力
- 批准号:
8440187 - 财政年份:2012
- 资助金额:
$ 50.87万 - 项目类别:
Testing the Therapeutic Potential of iPS Cells for Inherited Skin Diseases
测试 iPS 细胞对遗传性皮肤病的治疗潜力
- 批准号:
8896426 - 财政年份:2012
- 资助金额:
$ 50.87万 - 项目类别:
Testing the Therapeutic Potential of iPS Cells for Inherited Skin Diseases
测试 iPS 细胞对遗传性皮肤病的治疗潜力
- 批准号:
8546231 - 财政年份:2012
- 资助金额:
$ 50.87万 - 项目类别:
Regulation and Function of Keratins in the Epidermis
表皮角蛋白的调节和功能
- 批准号:
7847960 - 财政年份:2009
- 资助金额:
$ 50.87万 - 项目类别:
The Denver Network of the NHLBI Progenitor Cell Biology Consortium
NHLBI 祖细胞生物学联盟丹佛网络
- 批准号:
7678306 - 财政年份:2008
- 资助金额:
$ 50.87万 - 项目类别:
INDUCIBLE MOUSE MODELS FOR SKIN AND HEAD AND NECK CANCER
皮肤癌和头颈癌的诱导小鼠模型
- 批准号:
7123926 - 财政年份:2004
- 资助金额:
$ 50.87万 - 项目类别:
INDUCIBLE MOUSE MODELS FOR SKIN AND HEAD AND NECK CANCER
皮肤癌和头颈癌的诱导小鼠模型
- 批准号:
7922334 - 财政年份:2004
- 资助金额:
$ 50.87万 - 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:
$ 50.87万 - 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:
$ 50.87万 - 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:
$ 50.87万 - 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:
$ 50.87万 - 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:
$ 50.87万 - 项目类别:
Standard Grant
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:
$ 50.87万 - 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:
$ 50.87万 - 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:
$ 50.87万 - 项目类别:
EU-Funded
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:
$ 50.87万 - 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:
$ 50.87万 - 项目类别:
Research Grant














{{item.name}}会员




