Targeting mechanisms of immune evasion in chemotherapy-induced senescent cells
化疗诱导的衰老细胞免疫逃避的靶向机制
基本信息
- 批准号:10364840
- 负责人:
- 金额:$ 43.23万
- 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:2022-04-19 至 2027-02-28
- 项目状态:未结题
- 来源:
- 关键词:AddressAftercareApoptosisApoptoticBioinformaticsBreastBreast Cancer ModelBreast Cancer PatientCell AgingCell Cycle ArrestCell DeathCellsCessation of lifeClinicalClinical TrialsCombined Modality TherapyDataEffectivenessFailureGene ExpressionGene Expression ProfileGenesGoalsGrowthHarvestHumanImmuneImmune EvasionImmune TargetingImmune checkpoint inhibitorImmunohistochemistryImmunologicsImmunologyImmunotherapyInterferon Type IIInterferonsMalignant NeoplasmsMammary NeoplasmsMediatingMessenger RNAMitoticModelingMouse Mammary Tumor VirusMusNeoplasm TransplantationNutrientNutrient DepletionOncologistPathologicPatientsPhagocytesPharmaceutical PreparationsPhenotypePopulationProductionProteinsRelapseResearchResearch DesignResidual TumorsResistanceRetreatmentSamplingSeriesSignal TransductionSpecimenStainsStromal CellsT-LymphocyteTP53 geneTestingTherapeuticTransplantationTumor EscapeTumor-infiltrating immune cellsUp-Regulationanti-PD-L1anti-PD-L1 therapycancer therapycancer typecheckpoint inhibitionchemokinechemotherapycytokineexhaustionimmune clearanceimmunogenic cell deathimprovedin vivomalignant breast neoplasmmimeticsmouse modelmutantneoplastic cellnovelnovel strategiesnovel therapeuticsnutrient deprivationpredicting responsepredictive signaturepressurepreventprogrammed cell death ligand 1programsresponsesenescencesingle cell sequencingsingle-cell RNA sequencingstatisticstherapeutic targettriple-negative invasive breast carcinomatumor
项目摘要
Project Summary/Abstract
Breast tumors are rarely eradicated by chemotherapy. Residual disease exists for 2 reasons: the tumor cells 1)
avoid death from apoptosis, mitotic catastrophe, and nutrient deprivation; 2) avoid immune clearance. Our
previous research has established that by activating p53-mediated programs of arrest and senescence, tumor
cells avoid death by mitotic catastrophe, apoptosis, and nutrient deprivation. We showed chemotherapy treated
breast cancer patients with p53 wild type tumors have dismal survival compared to patients with p53 mutant
tumors. Senescent cells promote relapse by their production of cytokines and chemokines (termed the
senescence associated secretory phenotype, or SASP).
The weakness of prior research has been a failure to identify how the treated, senescent tumor cells avoid
immune clearance. In this proposal, we present compelling preliminary data addressing this weakness, and
plans to fully characterize and investigate potential therapeutic avenues that target the evasion of cell death,
thus facilitating immune clearance and improving survival. In preliminary data, we identify a remarkable
upregulation of PD-L1 in the persisting residual disease likely mediated through interactions with stromal cells,
and expression is maintained in the relapse, suggesting a strong selective pressure.
The goal of this project is to identify mechanisms and develop strategies to target immune evasion specifically
in tumor cells that have survived chemotherapy by entering senescence.
Hypothesis: Stromal interferon gamma (IFNγ) induces PD-L1 in a specific subset of cells in a chemotherapy-
treated, senescent tumor. These persisting, senescent tumor cells can be targeted using a novel strategy that
combines senolytic drugs to induce immunogenic cell death followed by immune checkpoint inhibitors.
In Aim 1 we will use mouse mammary tumor models to determine if PD-L1 expressing tumor cells have greater
relapse potential than cells within the same treated tumor that do not express PD-L1, and how each responds to
retreatment. We will characterize gene expression differences in cells that express PD-L1 vs. those that do not.
In Aim 2 we will identify the factors in vivo that are required for PD-L1 upregulation on senescent tumor cells.
We will transplant mammary tumors into syngeneic mice that lack specific immune components such as T cells,
treat with chemotherapy, and determine changes in PD-L1 expression and immune contexture.
In Aim 3, preliminary data show only one third of senescent mouse mammary tumors responded to anti-PD-L1
therapy following chemotherapy. We will test if inducing immunogenic cell death with BH3 mimetic drugs we
have shown to have senolytic activity can improve the response to immune checkpoint inhibitors.
In Aim 4, we will use multiplex immunohistochemistry staining of human breast cancer specimens pre and post
chemotherapy to determine if PD-L1 expression is induced in senescent tumors.
项目总结/文摘
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
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专利数量(0)
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James Jackson其他文献
James Jackson的其他文献
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{{ truncateString('James Jackson', 18)}}的其他基金
Targeting mechanisms of immune evasion in chemotherapy-induced senescent cells
化疗诱导的衰老细胞免疫逃避的靶向机制
- 批准号:
10611416 - 财政年份:2022
- 资助金额:
$ 43.23万 - 项目类别:
Genotoxic stress response and mutagenesis in normal tissues of mice deficient in homology directed repair
缺乏同源定向修复的小鼠正常组织中的基因毒性应激反应和诱变
- 批准号:
10555219 - 财政年份:2021
- 资助金额:
$ 43.23万 - 项目类别:
Genotoxic stress response and mutagenesis in normal tissues of mice deficient in homology directed repair
缺乏同源定向修复的小鼠正常组织中的基因毒性应激反应和诱变
- 批准号:
10211496 - 财政年份:2021
- 资助金额:
$ 43.23万 - 项目类别:
Genotoxic stress response and mutagenesis in normal tissues of mice deficient in homology directed repair
缺乏同源定向修复的小鼠正常组织中的基因毒性应激反应和诱变
- 批准号:
10388231 - 财政年份:2021
- 资助金额:
$ 43.23万 - 项目类别:
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