T cell responses shared among triple negative breast cancer patients
T cell responses shared among triple negative breast cancer patients
批准号:
9767747
负责人:
Jill E Slansky
金额:
$16.74万
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
已结题
起止时间:
2018-09-01 至 2021-12-31
关键词:
AddressAftercareAnimal ModelAntigensAntitumor ResponseBloodBreast Cancer PatientBreast Cancer TreatmentBreast Cancer cell lineBreast Cancer survivorCD8-Positive T-LymphocytesCancer BurdenCessation of lifeCharacteristicsClinicalDiagnosisDiseaseDisease-Free SurvivalERBB2 geneEstrogen ReceptorsEstrogensFutureGenerationsGoalsHLA-A2 AntigenHigh-Throughput Nucleotide SequencingHumanImmuneImmune systemImmunotherapyIn complete remissionKnowledgeLifeMaintenanceMemoryMethodsMissionMonitorMutateMutationNeoadjuvant TherapyNeoplasm MetastasisOutcomePathologicPatientsPredictive ValueProgesteroneProgesterone ReceptorsProliferatingPublic HealthRecurrenceResearchResidual CancersRiskSpecificitySurveysSurvivorsT cell responseT memory cellT-Cell ReceptorT-LymphocyteT-Lymphocyte SubsetsTissuesTreatment outcomeTumor AntigensUnited States National Institutes of HealthVaccinesWomanantigen-specific T cellsbreast cancer diagnosiscancer subtypeschemotherapydesigneffective therapyimmunotherapy clinical trialsimprovedlong term memorymalignant breast neoplasmmelanomamortalitymortality riskneoantigensoutcome forecastovertreatmentperipheral bloodprognostic valuereceptorresponseshared memorysurvivorshiptriple-negative invasive breast carcinomatumorvaccine development
中文摘要
项目摘要/摘要
三阴性乳腺癌(TNBC;雌激素受体、孕激素受体和HER2阴性)是
最致命的乳腺癌亚型。然而,相对于其他乳腺癌亚型,可以发现TNBCs
有许多肿瘤浸润性T细胞。这些T细胞的存在表明对肿瘤相关的反应
抗原。在这种反应中,一些肿瘤特异性T细胞增殖并分化为效应器,
中央或组织驻留的记忆T细胞。中央记忆T细胞寿命很长,可以找到
检查身体中是否有令人不快的抗原博尔赫斯博士和其他人最近表明,
确诊5年后,TNBC的死亡率急剧下降。然而,目前还不清楚哪些患者会
对治疗成功的反应以及哪些患者会复发。因此,迫切需要确定如何
这些T细胞可以被用于未来的治疗。在此,我们建议鉴定共享的T细胞受体
五年或以上的TNBC幸存者和正在接受治疗的患者。建议的总体目标是
研究是使用Slansky最近开发的一种方法来改进对TNBC患者的治疗
德科斯基实验室。他们使用高通量测序进行研究,发现一组共同的TCR
人类白细胞抗原A2+乳腺癌患者,但不是健康对照。肿瘤中共有的T细胞受体也是
在这些患者的外周血液中发现。此应用程序的总体目标是使用
识别应答患者共享T细胞应答的α-β记忆CD8 T细胞谱系
并确定标准治疗对T细胞的影响。这里讨论的中心假设是
可以确定TCR的常见亚群,这些亚群是在TNBC中存活的女性血液中独有的
超过5年,但没有复发妇女的血液。具体的目的是为了解决这一假设
(1)从TNBC幸存者的血液中鉴定共享记忆T细胞的T细胞受体;(2)
确定与病理完整相关的记忆T细胞谱系的纵向变化
治疗后反应。利用T细胞谱系理解长时记忆的产生
对TNBC的反应最终可能使TNBC的治疗发生革命性变化,因为它将为实现以下目标迈出第一步
可用于确定对维持无病至关重要的抗原的T细胞受体的鉴定
生存和其他治疗方法,可以提供持续的保护,防止存活多年后复发。
英文摘要
PROJECT SUMMARY/ABSTRACT
Triple negative breast cancer (TNBC; estrogen receptor-, progesterone receptor- and HER2-negative) is the
deadliest sub-type of breast cancer. However, relative to other breast cancer sub-types, TNBCs can be found
with many tumor infiltrating T cells. The presence of these T cells suggests a response to tumor-associated
antigens. From this response, some of the tumor-specific T cells proliferate and differentiate into effector,
central, or tissue-resident memory T cells. The central memory T cells are long-lived and can be found
surveying the body for the offending antigens. It was recently shown by Dr. Borges and others that the risk of
mortality from TNBC sharply decreases 5 years after diagnosis. However, it is unknown which patients will
respond successfully to therapy and which patients will recur. Thus, there is an urgent need to determine how
these T cells can be harnessed for future therapies. It is proposed here to identify shared T cell receptors of
TNBC survivors of five or more years and patients undergoing therapy. The overall goal of the proposed
research is to improve treatments for TNBC patients using a method recently developed by the Slansky and
DeKosky labs. They performed studies using high throughput sequencing, and found a panel of TCRs common
to HLA-A2+ breast cancer patients, but not healthy controls. The T cell receptors shared in tumors were also
identified in the peripheral blood of these patients. The overall objective of this application is to use the
repertoire of alpha-beta memory CD8 T cells to identify a shared T cell response among responder patients
and to determine the influence of standard therapy on T cells. The central hypothesis addressed here is that
common subsets of TCRs can be identified that are unique to the blood of women who have survived TNBC
more than 5 years, but not blood of women who have recurred. The specific aims to address this hypothesis
are: (1) to identify T cell receptors of shared memory T cells from the blood of TNBC survivors, and (2)
determine longitudinal changes in the memory T cell repertoire that correlate with a pathologic complete
response after treatment. Using the T cell repertoire to understand the generation of long-term memory
responses to TNBC may ultimately revolutionize treatment for TNBC, as it will provide the first steps toward
identification of T cell receptors that may be used to determine antigens critical to maintaining disease-free
survival and other therapies that can offer ongoing protection against recurrence for years into survivorship.
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会议论文
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资助金额:$40.54万
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资助金额:$27.75万
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依托单位:
Mouse Model for Antigen Specific Immunotherapy of Cancer
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批准号:7393729
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资助金额:$26.94万
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负责人:Jill E Slansky
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依托单位:
Mouse Model for Antigen Specific Immunotherapy of Cancer
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资助金额:$28.41万
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资助金额:$28.41万
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依托单位:
IMMUNODOMIANT PROPERTIES OF THE TUMOR ANTIGEN AH1
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负责人:Jill E Slansky
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IMMUNODOMIANT PROPERTIES OF THE TUMOR ANTIGEN AH1
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依托单位:
海外基金