Characterization of brain metastasis-specific CD8+ T cells
脑转移特异性 CD8 T 细胞的表征
基本信息
- 批准号:10680491
- 负责人:
- 金额:$ 13.25万
- 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:2022-08-09 至 2027-07-31
- 项目状态:未结题
- 来源:
- 关键词:AffectAntigensBiologyBrainCD8-Positive T-LymphocytesCTLA4 geneCancer PatientCell Differentiation processCellsCephalicCharacteristicsClinicalClustered Regularly Interspaced Short Palindromic RepeatsCytotoxic T-LymphocytesDataDevelopmentDisease ProgressionEffector CellExhibitsExposure toFailureGene ExpressionGene Expression ProfileGenesGenetic TranscriptionGoalsGrantHeterogeneityHumanImmuneImmunohistochemistryImmunotherapeutic agentImmunotherapyImpairmentInfectionInfiltrationIntracranial NeoplasmsLaboratoriesLymphocyteLymphocytic choriomeningitis virusMediatingMetastatic malignant neoplasm to brainModelingMolecularMorbidity - disease rateMusNeoplasm MetastasisPD-1 blockadePD-1 pathwayPathway interactionsPhenotypePopulationPopulation HeterogeneityPrevalenceProcessRefractoryResearchResistanceSolid NeoplasmSystemT cell infiltrationT-Cell ReceptorT-LymphocyteTestingTherapeuticTissue-Specific Gene ExpressionTissuesToxic effectTreatment EfficacyTumor AntigensTumor PromotionTumor-infiltrating immune cellsViralViral AntigensVirus DiseasesWorkcancer therapycell killingchronic infectioncytotoxic CD8 T cellscytotoxicitydifferential expressiondisorder controleffector T cellexhaustexhaustiongene functionimmune cell infiltrateimmune checkpoint blockadeimprovedmortalitymouse modelneoantigensneoplastic cellnovelnovel strategiesnovel therapeutic interventionperipheral bloodpreventprognostic significanceprogrammed cell death protein 1programsreceptorrecruitresponsestem cellstranscriptomicstreatment responsetumortumor microenvironment
项目摘要
PROJECT SUMMARY / ABSTRACT
CD8+ T cells are cytotoxic T lymphocytes that directly kill tumor and virally-infected cells. T cell exhaustion, in
which CD8+ T cells have impaired cell-killing capacity, occurs with prolonged exposure to viral and cancer
antigens and prevents optimal disease control. Immune checkpoint blockade (ICB) targeting CTLA-4 or the
PD-1 pathway reinvigorates exhausted CD8+ T cells to promote tumor cell killing. Multiple trials have
demonstrated the efficacy of ICB in shrinking or eliminating tumors and prolonging survival; however,
intracranial tumors are more refractory to ICB therapy than extracranial tumors. Brain metastases affect a
significant number of cancer patients and are associated with poor overall survival. Therefore, novel strategies
are urgently needed to improve the treatment of tumors that have metastasized to the brain.
Development of novel immunotherapeutic agents relies on a detailed characterization of CD8+ T cell
heterogeneity in brain metastases. My preliminary data show that there are three distinct populations of CD8+
T cells in human brain metastases, one of which is defined by a terminally differentiated transcriptional
phenotype. Using a murine chronic infection model, I have also demonstrated that brain-infiltrating antigen-
specific CD8+ T cells have a unique, tissue-specific transcriptional phenotype, which is conserved in a subset
of the CD8+ T cells infiltrating human brain metastases. Because of this differential gene expression pattern, I
hypothesize that there may be novel co-inhibitory molecules expressed by brain-infiltrating antigen-specific
CD8+ T cells. Blocking these molecules may improve therapeutic efficacy of PD-1 pathway blockade and
enhance the effector function of exhausted CD8+ T cells in the brain.
This project has three goals. First, I will comprehensively characterize the phenotype of CD8+ T cells
infiltrating human brain metastases and determine how clonotypes that are shared with circulating CD8+ T
cells respond to treatment with immunotherapies. Second, I will identify genes that are differentially expressed
by brain-infiltrating CD8+ T cells after ICB and test the function of these genes using the murine LCMV model
of CD8+ T cell exhaustion. Finally this grant will support my transition to independence from a trainee in Dr.
Rafi Ahmed’s lab, to leading an independent research group.
项目总结/摘要
CD 8 + T细胞是直接杀死肿瘤和病毒感染细胞的细胞毒性T淋巴细胞。T细胞耗竭,
其中CD 8 + T细胞具有受损的细胞杀伤能力,随着长期暴露于病毒和癌症而发生
抗原和阻止最佳的疾病控制。靶向CTLA-4的免疫检查点阻断(ICB)或
PD-1通路使耗尽的CD 8 + T细胞重新恢复活力,以促进肿瘤细胞杀伤。多项试验
证明了ICB在缩小或消除肿瘤和延长生存期方面的功效;然而,
颅内肿瘤比颅外肿瘤更难用ICB治疗。脑转移影响
癌症患者的数量显著增加,并且与较差的总体存活率相关。因此,新的战略
迫切需要改进对已经转移到大脑的肿瘤的治疗。
新型免疫抑制剂的开发依赖于CD 8 + T细胞的详细表征
脑转移瘤的异质性。我的初步数据显示,有三种不同的CD 8+细胞群体,
人脑转移瘤中的T细胞,其中之一是由终末分化的转录
表型使用小鼠慢性感染模型,我还证明了脑浸润抗原-
特异性CD 8 + T细胞具有独特的组织特异性转录表型,其在亚群中是保守的
的CD 8 + T细胞浸润人脑转移瘤。由于这种差异基因表达模式,我
假设脑浸润性抗原特异性表达的新的共抑制分子,
CD 8 + T细胞。阻断这些分子可以改善PD-1通路阻断的治疗功效,
增强脑中耗尽的CD 8 + T细胞的效应子功能。
该项目有三个目标。首先,我将全面描述CD 8 + T细胞的表型
浸润性人脑转移瘤,并确定如何与循环CD 8 + T共享克隆型,
细胞对免疫疗法有反应。第二,我将识别差异表达的基因,
通过ICB后脑浸润的CD 8 + T细胞,并使用小鼠LCMV模型测试这些基因的功能
CD 8 + T细胞衰竭。最后,这笔赠款将支持我从博士的实习生过渡到独立。
拉菲·艾哈迈德的实验室,领导一个独立的研究小组。
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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Lisa Sudmeier其他文献
Lisa Sudmeier的其他文献
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{{ truncateString('Lisa Sudmeier', 18)}}的其他基金
Characterization of brain metastasis-specific CD8+ T cells
脑转移特异性 CD8 T 细胞的表征
- 批准号:
10525753 - 财政年份:2022
- 资助金额:
$ 13.25万 - 项目类别:
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