T Cell-Specific BRCA1 Function in Antitumor Immunity and Immunotherapy
T 细胞特异性 BRCA1 在抗肿瘤免疫和免疫治疗中的功能
基本信息
- 批准号:10716957
- 负责人:
- 金额:$ 61.46万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-07-15 至 2028-06-30
- 项目状态:未结题
- 来源:
- 关键词:AffectAgeAttenuatedBRCA1 MutationBRCA1 geneBreast Epithelial CellsCD8-Positive T-LymphocytesCancer BiologyCancer EtiologyCellsCellular biologyClinicalComplementCoupledDNA Double Strand BreakDNA RepairDataDefectDevelopmentDimensionsDouble Strand Break RepairEpitheliumFoundationsGeneticGenomic InstabilityGerm-Line MutationHeterozygoteHumanImmuneImmune EvasionImmune systemImmunotherapyImpairmentIncidenceKnock-outKnowledgeLabelLaboratory FindingMalignant NeoplasmsMass Spectrum AnalysisMature T-LymphocyteMolecularMusNeoplasmsOncogenesOperative Surgical ProceduresPositioning AttributeResearchRiskRisk ReductionRoleSamplingSomatic CellT-LymphocyteTechnologyTestingTimeTranscriptional RegulationTumor ImmunityTumor Suppressor ProteinsWomanWorkbreast tumorigenesiscancer immunotherapycancer preventioncancer riskcohortdriving forceepithelial repairexperimental studygenomic toolslifetime riskmalignant breast neoplasmmammary epitheliummouse geneticsmultidisciplinarymutantmutant mouse modelmutation carriermutational statusneoplasm immunotherapyneoplastic cellnovelpreclinical studyprophylacticrepairedresponsetooltranslational impacttumortumor immunologytumorigenesisvirtual
项目摘要
ABSTRACT
Women with germline mutations of BRCA1 have about an 80% lifetime risk of developing breast cancer. All
somatic cells in a germline BRCA1 mutation carrier harbor the same mutant copy of the BRCA1 gene, yet BRCA1
research is almost exclusively focused on BRCA1’s role in repair of double-strand DNA breaks in the breast
epithelium. This is due to the cardinal tenet of the current BRCA1 paradigm — increased genetic instability of
the breast epithelium solely drives development of BRCA1 mutation-related breast cancer. In addition, current
prophylactic risk-reducing surgeries are aimed at curtailing tumorigenesis of breast epithelial cells of BRCA1
mutation carriers. In contrast, virtually nothing is known about whether BRCA1 heterozygosity in cells beyond
the breast epithelium could also contribute to BRCA1-related tumorigenesis.
Neoplasia is antagonized by the ability of the immune system to detect and eliminate neoplastic cells. Clearly,
impaired antitumor immunity enables immune evasion and tumor outgrowth. We recently found that women with
BRCA1 germline mutations have less abundant circulating CD8+ T cells versus age-matched donors with wild-
type BRCA1 genes. In support of this clinical finding, heterozygous knockout of Brca1 specifically in CD8+ T cells
of mice is sufficient to attenuate antitumor immunity. Based on our preliminary data, we hypothesize that T cell-
intrinsic function of BRCA1 in enhancing antitumor immunity contributes to the overall tumor
suppressor activity of BRCA1. We further propose that in BRCA1 mutation carriers, increased genomic
instability in the breast epithelium and attenuated antitumor immunity in CD8+ T cells act together to elevate
cancer incidence. To validate this novel hypothesis, we will combine our established team’s tools and expertise
in cancer biology, tumor immunology, and transcriptional regulation through the following three Specific Aims:
(1) Discern the impact of T cell-intrinsic BRCA1 on antitumor immunity and immunotherapy, (2) Elucidate the
molecular basis for BRCA1’s function in antitumor immunity, and (3) Examine BRCA1 mutation-related T cell
deficiency in human samples.
Our proposed work represents a new direction in elucidating a previously unappreciated tumor-suppressing
function of BRCA1 in immune cells. The concept to be validated clearly departs from the prevailing paradigm
regarding BRCA1-related cancer etiology, which is focused on the breast epithelium and DNA repair. From a
translational perspective, our proposed study focusing on BRCA1 in immune cells will likely inform development
of novel immune-boosting strategies for women with BRCA1 germline mutations. Thus, this line of work has
potential for far-reaching and sustained impact on breast cancer cancer risk reduction.
摘要
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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YANFEN HU其他文献
YANFEN HU的其他文献
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{{ truncateString('YANFEN HU', 18)}}的其他基金
A Dual Functional Switch in Reproductive Biology
生殖生物学中的双功能开关
- 批准号:
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- 资助金额:
$ 61.46万 - 项目类别:
Role of BRCA1 phosphorylation in DNA DSB repair and genome stability maintenance
BRCA1 磷酸化在 DNA DSB 修复和基因组稳定性维持中的作用
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9753187 - 财政年份:2017
- 资助金额:
$ 61.46万 - 项目类别:
Role of BRCA1 phosphorylation in DNA DSB repair and genome stability maintenance
BRCA1 磷酸化在 DNA DSB 修复和基因组稳定性维持中的作用
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10251866 - 财政年份:2017
- 资助金额:
$ 61.46万 - 项目类别:
Role of BRCA1 phosphorylation in DNA DSB repair and genome stability maintenance
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- 资助金额:
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