Cancer Cell Intrinsic Interferon-I pathway Activation by Fractionated Radiation
Cancer Cell Intrinsic Interferon-I pathway Activation by Fractionated Radiation
批准号:
9207065
负责人:
Sandra Demaria
金额:
$38.77万
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:
2016-01-19 至 2020-12-31
关键词:
4T1AcuteAddressAffectAftercareAntigensAntineoplastic AgentsBone MarrowBreast Cancer CellCD8-Positive T-LymphocytesCancer PatientCancer SurvivorCancer VaccinesCarcinomaCell DeathCellsChimera organismClinicCyclic GMPCytotoxic T-Lymphocyte-Associated Protein 4DNADataDendritic CellsDendritic cell activationDevelopmentDoseDose FractionationEpitopesFunctional disorderGap JunctionsGene ActivationGenerationsGenesHematopoieticHumanIFNAR1 geneImmuneImmune checkpoint inhibitorImmune responseImmunocompetentImmunologic AdjuvantsImmunosuppressive AgentsImmunotherapyImplantIn SituIndividualInfiltrationInterferon Type IInterferonsIonizing radiationIrradiated tumorKnowledgeLigandsMC38MCF7 cellMDA MB 231Malignant Epithelial CellMediatingModalityModelingMolecularMusMutateMutationMyeloid CellsNeoplasm MetastasisNeoplastic Epithelial CellPathway interactionsPatientsPhenotypePre-Clinical ModelProteinsRadiationRadiation therapyRecruitment ActivityRegimenRoleSignal TransductionT cell responseT-Cell ActivationT-LymphocyteTestingTherapeuticTumor AntigensTumor ImmunityVaccinatedVaccinationVaccinesVirus DiseasesWild Type MouseWorkadvanced diseasecancer cellcancer therapycarcinogenesischemotherapyexperimental studyimmune checkpointimmune checkpoint blockadeimmunogenicimprovedin vitro testingin vivoknock-downneoplastic cellnovelnovel strategiesoverexpressionpre-clinicalpublic health relevancereceptorresponsesensorsmall hairpin RNAsuccesstumortumor microenvironment
中文摘要
英文摘要
DESCRIPTION (provided by applicant): Recent evidence indicates that the most powerful anti-tumor T cells recognize neoantigens derived from unique mutated proteins expressed by an individual tumor, suggesting that precision vaccination is required to induce effective anti-tumor immunity in cancer patients. Importantly, such anti-tumor T cells cause tumor regression at advanced disease stages upon therapeutic immune checkpoints blockade. We have pioneered studies exploring the use of local tumor radiotherapy (RT) as a means to generate an in situ individualized vaccine. We were the first to demonstrate in a pre-clinical model that RT sensitizes unresponsive tumors to CTLA-4 blockade by inducing T cells specific for endogenous tumor antigens. Emerging evidence by us and others suggests a similar effect of RT in the clinic. However, lack of knowledge about the mechanisms involved precludes rapid progress towards the effective use of RT as an immune adjuvant. One critical unanswered question is whether dose and fractionation affect RT ability to elicit anti-tumor immune responses. We have previously found in two mouse carcinomas that generation of an in situ vaccine synergistic with anti-CTLA-4 treatment in inducing immune-mediated regression of irradiated and synchronous non-irradiated tumors (abscopal effect) was achieved by RT given in 3 fractions of 8 Gy but not by a single 20 Gy dose, suggesting that the RT regimen employed is critical. We now have data supporting the hypothesis that carcinoma cell-intrinsic activation of type I interferon (IFN-I) pathway by RT is required to generate an in situ vaccine, suggesting that RT triggers canonical defense pathways in neoplastic epithelial cells that mimic a viral infection. Our data also indicat that fractionated (FRT) but not single dose (SDRT) radiation can accomplish this via activation of the cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS) and downstream stimulator of IFN genes (STING) within the irradiated cancer cells. To test the above hypothesis several mouse and human carcinoma cells will be employed to determine which RT dose/fractionation activates cGAS/STING. Next, in vivo experiments using cancer cells with selective knockdown of cGAS or STING implanted in syngeneic immunocompetent wild type, cGAS-deficient, and STING-deficient mice will be performed to determine the role of this pathway in RT-mediated induction of anti-tumor T cells that mediate tumor regression and abscopal responses. To determine whether the effects of IFN-I produced by irradiated cancer cells are cancer cell autonomous or require signaling in host DC, IFNAR1-deficient mice will be used as tumor recipient. The relationship between cancer cell-derived IFN-I and DC recruitment to tumors will be established. Finally, we will investigate the mechanisms whereby RT activates the cGAS/STING pathway in cancer cells. Overall, data obtained will have important implications for a novel use of radiotherapy as a relatively simple and widely available modality for individualized tumor vaccination.
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会议论文
Hypoxic incubator for physiological cell culture research
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批准号:10427609
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项目类别:
-
资助金额:$10.45万
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财政年份:2022
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负责人:Sandra Demaria
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依托单位:
Individualized in situ vaccination by radiation and immunotherapy
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批准号:9127533
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项目类别:
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资助金额:$40.51万
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财政年份:2016
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负责人:Sandra Demaria
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依托单位:
Cancer Cell Intrinsic Interferon-I pathway Activation by Fractionated Radiation
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批准号:9009692
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项目类别:
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资助金额:$38.77万
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财政年份:2016
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负责人:Sandra Demaria
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依托单位:
Cancer Cell Intrinsic Interferon-I pathway Activation by Fractionated Radiation
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批准号:10366757
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项目类别:
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资助金额:$40.52万
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财政年份:2016
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负责人:Sandra Demaria
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依托单位:
Individualized in situ vaccination by radiation and immunotherapy
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批准号:9904135
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项目类别:
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资助金额:$38.77万
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财政年份:2016
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负责人:Sandra Demaria
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依托单位:
Cancer Cell Intrinsic Interferon-I pathway Activation by Fractionated Radiation
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批准号:10706961
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项目类别:
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资助金额:$39.71万
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财政年份:2016
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负责人:Sandra Demaria
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依托单位:
Local Radiation as an Adjuvant for Immunotherapy
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批准号:7263431
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项目类别:
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资助金额:$31.93万
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财政年份:2007
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负责人:Sandra Demaria
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依托单位:
Local Radiation as an Adjuvant for Immunotherapy
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批准号:7760656
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项目类别:
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资助金额:$32.21万
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财政年份:2007
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负责人:Sandra Demaria
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依托单位:
Local Radiation as an Adjuvant for Immunotherapy
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批准号:7383133
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项目类别:
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资助金额:$32.21万
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财政年份:2007
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负责人:Sandra Demaria
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依托单位:
Local Radiation as an Adjuvant for Immunotherapy
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批准号:8020091
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项目类别:
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资助金额:$31.24万
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财政年份:2007
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负责人:Sandra Demaria
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依托单位:
Local Radiation as an Adjuvant for Immunotherapy
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批准号:7547386
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项目类别:
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资助金额:$32.21万
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财政年份:2007
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负责人:Sandra Demaria
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依托单位:
TUMOR APOPTOSIS AS MAJOR DETERMINANT OF IMMUNOGENICITY
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批准号:6514844
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项目类别:
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资助金额:$6.84万
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财政年份:2001
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负责人:Sandra Demaria
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依托单位:
TUMOR APOPTOSIS AS MAJOR DETERMINANT OF IMMUNOGENICITY
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批准号:6837643
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项目类别:
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资助金额:$13.69万
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财政年份:2001
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负责人:Sandra Demaria
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依托单位:
TUMOR APOPTOSIS AS MAJOR DETERMINANT OF IMMUNOGENICITY
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批准号:6399182
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项目类别:
-
资助金额:$13.69万
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财政年份:2001
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负责人:Sandra Demaria
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依托单位:
TUMOR APOPTOSIS AS MAJOR DETERMINANT OF IMMUNOGENICITY
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批准号:7005373
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项目类别:
-
资助金额:$6.84万
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财政年份:2001
-
负责人:Sandra Demaria
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依托单位:
TUMOR APOPTOSIS AS MAJOR DETERMINANT OF IMMUNOGENICITY
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批准号:6649733
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项目类别:
-
资助金额:$13.69万
-
财政年份:2001
-
负责人:Sandra Demaria
-
依托单位:
TUMOR APOPTOSIS AS MAJOR DETERMINANT OF IMMUNOGENICITY
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批准号:6694084
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项目类别:
-
资助金额:$13.69万
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财政年份:2001
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负责人:Sandra Demaria
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依托单位:
海外基金