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一种
项目成果
期刊论文数量(0)
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Dennis Roop其他文献
Dennis Roop的其他文献
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{{ 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:
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