NK cell exhaustion in metastatic melanoma
NK cell exhaustion in metastatic melanoma
批准号:
9177359
负责人:
Nina Bhardwaj
金额:
$40.36万
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-07-27 至 2021-06-30
关键词:
AddressAdoptive TransferAdvanced Malignant NeoplasmAnimalsAntibodiesAntigensBiological MarkersBloodCD80 geneCell physiologyCellsCellular biologyClinicalCytolysisCytotoxic T-Lymphocyte-Associated Protein 4DefectDevelopmentDiseaseEffector CellEquilibriumFailureFunctional disorderGrowthHumanImmuneImmune responseImmunityImmunosuppressionIn VitroInfiltrationInterferon Type IIInterventionLigandsMalignant NeoplasmsMelanoma CellMetastatic MelanomaModelingMolecularMusNatural ImmunityNatural Killer CellsPDCD1LG1 geneParticipantPatientsPhenotypePhosphoric Monoester HydrolasesProcessProductionProliferatingProtein DephosphorylationProteinsReceptor ActivationReceptor SignalingRiskSignal TransductionSiteStagingT-Cell ActivationT-Cell ReceptorT-LymphocyteT-bet proteinTestingTumor TissueVirus Diseasesadaptive immunitycancer therapycytokinecytotoxicexhaustexhaustionimmunological synapsein vivokillingsmelanomamouse modelperipheral bloodreceptorresponserestorationtraffickingtumortumor growthtumor microenvironmenttumorigenesis
中文摘要
项目总结
英文摘要
Project summary
NK cells are key participants in the initial immune response to tumorigenesis and virus infections,
equipped to respond rapidly through induction of cytokines and deployment of cytotoxic activity. A dynamic
balance of positive and negative signals regulates NK cell target cell recognition and lysis, through
engagement of a variety of activation and inhibitory receptors. However, as cancers advance there is
accumulating evidence that NK cells become progressively dysfunctional. NK cell “exhaustion,” could explain
the failure of NK cells to contain tumor growth in advanced cancers. While NK cell hyporesponsiveness has
been described in various malignancies, there is little characterization of an “exhausted NK cell state” in
metastatic disease, nor of the mechanisms that might underlie this phenotype. We now have evidence that NK
cells progressively undergo exhaustion in late stage melanoma. Melanoma associated NK cells are
characterized by a failure to proliferate, to produce interferon gamma (IFNγ) or to kill target cells. They (i) down
regulate activation receptors, IL-2R subunits and NK cell regulatory transcription factors (T-bet, Eomes), (ii)
upregulate inhibitory receptors and (iii) express high levels of the checkpoint molecule Tim-3, a phenotype that
is consistent with “NK cell exhaustion”. Significantly, blockade of Tim-3 substantially reverses this phenotype
and state of exhaustion in vitro (Can. Imm Res. 2014). Most strikingly however, we find that patients who have
a clinical response to ipilimumab treatment spontaneously restore their NK cell function, despite the fact that
these cells express little or no CTLA-4 (or PD-1 or PD-L1), possibly through reversal of tumor-associated
systemic immune suppression. Characterizing NK cell dysfunction in melanoma, therefore, will be critical to
understanding the modulation of NK cell biology in the tumor microenvironment (TME), and ultimately towards
developing approaches that restore both innate and adaptive immunity, in vivo.
Although the survival of advanced melanoma patients (stage IV) has been extended by interventions
that reverse T cell exhaustion, we hypothesize that reversal of exhaustion in NK cells will contribute towards
the full restoration of immune responses that are required to eliminate melanoma cells. To address this
hypothesis, we aim to define the spectrum of NK cell exhaustion in melanoma and identify molecular/protein
targets that potentiate NK cell exhaustion (Aim 1). Secondly, we will determine if NK cell exhaustion can be
reversed in response to checkpoint blockade inhibition, and identify associated biomarkers (Aim 2). In Aim 3,
we will develop murine models to define and test interventions that reverse NK cell exhaustion. Characterizing
NK cell dysfunction in melanoma will be critical towards developing approaches that restore immunity, in vivo.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
The Tisch Cancer Institute (TCI) Paul Calabresi K12 Career Development Award for Clinical Oncology
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批准号:10434380
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项目类别:
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资助金额:$5.4万
-
财政年份:2022
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负责人:Nina Bhardwaj
-
依托单位:
The Tisch Cancer Institute (TCI) Paul Calabresi K12 Career Development Award for Clinical Oncology
-
批准号:10623252
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项目类别:
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资助金额:$56.69万
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财政年份:2022
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负责人:Nina Bhardwaj
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依托单位:
Dissecting myeloid cell-mediated resistance to immune checkpoint blockade in bladder cancer
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批准号:10652272
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项目类别:
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资助金额:$68.93万
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财政年份:2020
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负责人:Nina Bhardwaj
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依托单位:
Dissecting myeloid cell-mediated resistance to immune checkpoint blockade in bladder cancer
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批准号:10380068
-
项目类别:
-
资助金额:$68.93万
-
财政年份:2020
-
负责人:Nina Bhardwaj
-
依托单位:
Effect of SARS-CoV-2 on clinical course and NK cells in patients receiving immunotherapy
-
批准号:10203557
-
项目类别:
-
资助金额:$16.84万
-
财政年份:2020
-
负责人:Nina Bhardwaj
-
依托单位:
Cancer Immunology
-
批准号:10454170
-
项目类别:
-
资助金额:$2.63万
-
财政年份:2015
-
负责人:Nina Bhardwaj
-
依托单位:
Cancer Immunology (CI) (Project-001)
-
批准号:8932191
-
项目类别:
-
资助金额:$0.93万
-
财政年份:2015
-
负责人:Nina Bhardwaj
-
依托单位:
Cancer Immunology
-
批准号:10674510
-
项目类别:
-
资助金额:$2.63万
-
财政年份:2015
-
负责人:Nina Bhardwaj
-
依托单位:
Cancer Immunology
-
批准号:10022663
-
项目类别:
-
资助金额:$2.63万
-
财政年份:2015
-
负责人:Nina Bhardwaj
-
依托单位:
Matrix metalloproteinase-2 modulates inflammation via TLR2
-
批准号:8777819
-
项目类别:
-
资助金额:$35.17万
-
财政年份:2014
-
负责人:Nina Bhardwaj
-
依托单位:
Matrix metalloproteinase-2 modulates inflammation via TLR2
-
批准号:8874174
-
项目类别:
-
资助金额:$35.17万
-
财政年份:2014
-
负责人:Nina Bhardwaj
-
依托单位:
Modulating anti-HIV immunity by plasmacytoid dendritic cells
-
批准号:8744629
-
项目类别:
-
资助金额:$33.86万
-
财政年份:2013
-
负责人:Nina Bhardwaj
-
依托单位:
Induction of Immunity by Non-Replicating HIV-1
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批准号:8744626
-
项目类别:
-
资助金额:$22.12万
-
财政年份:2013
-
负责人:Nina Bhardwaj
-
依托单位:
NIAID Clinical Trial Planning Grant
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批准号:8211593
-
项目类别:
-
资助金额:$28.61万
-
财政年份:2011
-
负责人:Nina Bhardwaj
-
依托单位:
Innate Discovery Team
-
批准号:8294657
-
项目类别:
-
资助金额:$120.4万
-
财政年份:2011
-
负责人:Nina Bhardwaj
-
依托单位:
Modulating anti-HIV immunity by plasmacytoid dendritic cells
-
批准号:8240408
-
项目类别:
-
资助金额:$41.83万
-
财政年份:2010
-
负责人:Nina Bhardwaj
-
依托单位:
Modulating anti-HIV immunity by plasmacytoid dendritic cells
-
批准号:8436297
-
项目类别:
-
资助金额:$39.31万
-
财政年份:2010
-
负责人:Nina Bhardwaj
-
依托单位:
Exposing virus-induced long noncoding RNA in plasmacytoid dendritic cells
-
批准号:10239219
-
项目类别:
-
资助金额:$42.38万
-
财政年份:2010
-
负责人:Nina Bhardwaj
-
依托单位:
Modulating anti-HIV immunity by plasmacytoid dendritic cells
-
批准号:8058751
-
项目类别:
-
资助金额:$41.83万
-
财政年份:2010
-
负责人:Nina Bhardwaj
-
依托单位:
Modulating anti-HIV immunity by plasmacytoid dendritic cells
-
批准号:8651406
-
项目类别:
-
资助金额:$41.63万
-
财政年份:2010
-
负责人:Nina Bhardwaj
-
依托单位:
海外基金