Regulation of Tumor Microenvironment in Cancer
Regulation of Tumor Microenvironment in Cancer
批准号:
8856524
负责人:
SCOTT J. ANTONIA
金额:
$37.36万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2014
资助国家:
美国
项目状态:
已结题
起止时间:
2014-06-01 至 2017-05-31
关键词:
3-nitrotyrosineAddressAntibodiesAntigen PresentationAntigensApoptosisBindingCD8 AntigensCancer PatientCell physiologyCharacteristicsClinicalCysteineCytotoxic T-LymphocytesDataDevelopmentFree Radical FormationHealthHistocompatibility Antigens Class IImmuneImmune responseImmunotherapyInflammationInflammatory ResponseLung NeoplasmsMalignant NeoplasmsMalignant neoplasm of lungMethionineMethodsModelingMusMyelogenousMyeloid CellsNitric OxideNitrogenNon-Small-Cell Lung CarcinomaOxygenPatientsPeptide/MHC ComplexPeptidesPeripheralPeroxonitritePharmaceutical PreparationsPhase I/II TrialPlayProductionProteinsRecruitment ActivityRegulationResistanceRoleSamplingSignal TransductionSuperoxidesSuppressor-Effector T-LymphocytesSurfaceT cell responseT-Cell ReceptorT-LymphocyteTestingTissuesTryptophanTumor AntigensTumor EscapeTyrosineUp-RegulationVaccinesbasecancer cellcancer immunotherapyclinically relevantclinically significantgranulocyteimprovedinhibitor/antagonistkillingsmacrophagemouse modelneoplastic cellnitrationnovelnovel strategiespre-clinicalreceptorresponsesuccesstumortumor microenvironment
中文摘要
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英文摘要
DESCRIPTION (provided by applicant): In recent years, advances in cancer immunotherapy make it possible to induce tumor-specific immune responses in patients treated with various types of cancer immunotherapy. However, despite these successes, the proportion of patients who benefit clinically from these treatments remains small. It is clear that the tumor microenvironment may provide protection of tumors even against potent cytotoxic T cell (CTL) responses. Inflammation associated with the tumor microenvironment plays an important role in the development and progression of lung cancer. In the context of an inflammatory response myeloid cells are the primary recruited effectors. Production of reactive oxygen (ROS) and nitrogen (RNS) species is one of the major characteristics of all activated myeloid cells. The formation of the free radical peroxynitrite (PNT) is the main result of interaction between superoxide and nitric oxide. Nitration of tyrosine residues has long been recognized as a marker of PNT activity. In addition, PNT can react directly with cysteine, methionine and tryptophan. A substantial number of studies have demonstrated high levels of nitrotyrosine (NT) in lung cancer. Recently, we have proposed a novel concept that may explain the role of inflammation in tumor escape. The tumor-infiltrating myeloid cells, particularly myeloid-derived suppressor cells, can induce nitration of MHC class I molecules on tumor cells, making them unable to effectively bind and retain peptides and thus rendering the tumor cells resistant to antigen-specific CTLs. This concept suggests that tumors may escape immune control even if potent CTL responses against the tumor-associated antigens were generated either by vaccines, T-cell transfer, or checkpoint inhibitors. It also suggests that this escape can be diminished by blocking the PNT production using pharmacological inhibitors of ROS or RNS. Based on our previous and preliminary data we propose that inhibition of ROS and RNS in the tumor microenvironment can enhance the effect of cancer immune therapy. In this application we will test this hypothesis.
Specific aim 1. To determine the mechanism of peroxynitrite effects on tumor escape;
Specific aim 2. To determine in mouse tumor models the combine effect of a blocking PD1 antibody with a novel triterpenoid RTA 408;
Specific aim 3. To determine clinical significance of up-regulation of reactive oxygen and nitrogen species in lung tumors.
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会议论文
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财政年份:2018
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Targeting the adenosine A2A receptor immune checkpoint in lung cancer patients
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批准号:9175600
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财政年份:2016
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Targeting the adenosine A2A receptor immune checkpoint in lung cancer patients
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批准号:9462266
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财政年份:2016
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负责人:SCOTT J. ANTONIA
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依托单位:
Development of Immunotherapeutic Strategies in the Treatment of Lung Cancer
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批准号:7921307
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资助金额:$10.96万
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财政年份:2009
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负责人:SCOTT J. ANTONIA
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依托单位:
Development of Immunotherapeutic Strategies in the Treatment of Lung Cancer
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批准号:8311051
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项目类别:
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资助金额:$17.12万
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财政年份:2008
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负责人:SCOTT J. ANTONIA
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依托单位:
Development of Immunotherapeutic Strategies in the Treatment of Lung Cancer
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批准号:7676762
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项目类别:
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资助金额:$16.45万
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财政年份:2008
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负责人:SCOTT J. ANTONIA
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依托单位:
Development of Immunotherapeutic Strategies in the Treatment of Lung Cancer
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批准号:8139718
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项目类别:
-
资助金额:$17.12万
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财政年份:2008
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负责人:SCOTT J. ANTONIA
-
依托单位:
Development of Immunotherapeutic Strategies in the Treatment of Lung Cancer
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批准号:7471963
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项目类别:
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资助金额:$16.13万
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财政年份:2008
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负责人:SCOTT J. ANTONIA
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依托单位:
Combination Immunotherapy for Lung Cancer
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批准号:7111269
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项目类别:
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资助金额:$28.93万
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财政年份:2006
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负责人:SCOTT J. ANTONIA
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依托单位:
Combination Immunotherapy for Lung Cancer
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批准号:7282732
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项目类别:
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资助金额:$28.09万
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财政年份:2006
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负责人:SCOTT J. ANTONIA
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依托单位:
B7 1 GENE MODIFIED TUMOR CELL VACCINE FOR RENAL CELL CA
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批准号:6153452
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项目类别:
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资助金额:$7.25万
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财政年份:2000
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负责人:SCOTT J. ANTONIA
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依托单位:
B7 1 GENE MODIFIED TUMOR CELL VACCINE FOR RENAL CELL CA
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批准号:6377276
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项目类别:
-
资助金额:$7.25万
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财政年份:2000
-
负责人:SCOTT J. ANTONIA
-
依托单位:
Precision Cancer Medicine and Investigational Therapeutics
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批准号:10323317
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项目类别:
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资助金额:$6.72万
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财政年份:1997
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负责人:SCOTT J. ANTONIA
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依托单位:
Precision Cancer Medicine and Investigational Therapeutics
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批准号:10544834
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项目类别:
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资助金额:$6.76万
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财政年份:1997
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负责人:SCOTT J. ANTONIA
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依托单位:
IMMUNE TOLERANCE INDUCTION BY A TUMOR SPECIFIC ANTIGEN
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批准号:3086013
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项目类别:
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资助金额:$1.36万
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财政年份:1994
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负责人:SCOTT J. ANTONIA
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依托单位:
IMMUNE TOLERANCE INDUCTION BY A TUMOR SPECIFIC ANTIGEN
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批准号:2103305
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项目类别:
-
资助金额:$9.42万
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财政年份:1994
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负责人:SCOTT J. ANTONIA
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依托单位:
海外基金