Project 2: Measuring and modeling the tumor and immune microenvironment before and during therapy and at the time of drug resistance
Project 2: Measuring and modeling the tumor and immune microenvironment before and during therapy and at the time of drug resistance
批准号:
10343840
负责人:
Arlene H. Sharpe
金额:
$30.14万
依托单位:
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:
2018-03-08 至 2023-02-28
关键词:
Adrenal Cortex HormonesAdverse effectsAdverse eventAdverse reactionsAntibodiesAntigensBRAF geneBiologicalBiological AssayBiological MarkersBiopsyBrain NeoplasmsBullous PemphigoidCTLA4 geneCell CycleCellsClinicalClinical TrialsComplementComputing MethodologiesDNA DamageDNA damage checkpointDataDisease ProgressionDisease ResistanceDrug resistanceEcosystemExcisionExtracellular MatrixFormalinGenerationsGenomic InstabilityGoalsHomeostasisHumanImageImmuneImmune System DiseasesImmune ToleranceImmune checkpoint inhibitorImmunofluorescence ImmunologicImmunohistochemistryImmunologic SurveillanceInfiltrationInstitutional Review BoardsInterventionIntervention StudiesLearningLichen PlanusLigandsLightLinkMEKsMeasuresMessenger RNAMethodsModelingMolecularMusNon-MalignantParaffin EmbeddingPatientsPeriodicityPharmaceutical PreparationsPharmacologyPhenotypePhosphotransferasesPhysiologyPrediction of Response to TherapyPropertyProteinsPsoriasisReactionReagentResectedResistanceResolutionRetinoidsSamplingSeveritiesSignal TransductionSkinSpecimenSteroidsStromal CellsStromal NeoplasmSupervisionSystemT-LymphocyteTNF geneTestingTherapeuticTherapeutic InterventionTimeTime Series AnalysisTissue EmbeddingTissuesToxic effectTreatment EffectivenessTriplet Multiple BirthTumor MarkersTumor-Infiltrating LymphocytesTumor-infiltrating immune cellsVitiligoWorkalgorithm developmentarmbasebevacizumabcancer cellcell stromacell typecohorteffectiveness evaluationfluorescence imaginghigh dimensionalityhuman imagingimaging modalityimmune checkpointinhibitorinsightmachine learning methodmalignant statemelanomamouse modelmultidimensional datamutational statusneoplastic cellnovelopen sourcephenotypic datapredicting responseprogrammed cell death ligand 1programmed cell death protein 1responseresponse biomarkersingle cell sequencingsingle-cell RNA sequencingsmall moleculesoftware developmenttargeted agenttargeted treatmenttranscriptomicstreatment responsetriple-negative invasive breast carcinomatumortumor microenvironmenttumor-immune system interactionsunsupervised learning
中文摘要
项目摘要-项目2(目标5)肿瘤和免疫系统的测量和建模
英文摘要
PROJECT SUMMARY – PROJECT 2 (AIM 5) Measuring and modeling the tumor and immune
microenvironment before and after therapy. The overall goal of Project 2 is to determine which features of a
tumor and its microenvironment make it responsive to ICIs or targeted therapies alone or in combination. We
will collect quantitative data at single cell resolution on the identities, states and physical arrangement of tumor,
stromal and immune cells and on soluble and ECM components that comprise the tumor microenvironment
(TME). This will be accomplished using highly multiplexed fluorescence imaging of standard formalin fixed,
paraffin-embedded (FFPE) tissue and tumor samples combined with single cell RNA sequencing (scRNA). To
provide insight into causal relationships among variables, we will analyze samples collected at different points
in time, most commonly biopsies prior to and on therapy, and at the time of drug-resistant disease. In the case
of ICI-induced skin toxicities, we will perform localized interventional studies (e.g. treatment with retinoids)
followed by biopsies to determine the effectiveness of treatment and to test specific hypotheses about immune
cell homeostasis in skin, respectively. Much of the work in this project will be hypothesis generating and will be
tightly integrated with hypothesis testing studies in cells and mice in Projects 1 and 3.
Aim 5.1 will focus on experimental and computational methods for obtaining 20-60 channel images from
formalin-fixed, paraffin embedded (FFPE) tissue and tumor samples using tissue-based cyclic
immunofluorescence (t-CycIF). Aim 5.2 will integrate high dimensional t-CycIF imaging and single cell RNA
sequencing to generate data on the composition and states of tumor, stromal and immune cells at single-cell
resolution (“deep tumor phenotypes”). Aim 5.3 will use deep phenotyping to analyze tumors from BRAFV600E
patients treated with BRAF and MEK inhibitors or patients treated with ICIs irrespective of the BRAF mutation
status. Biopsies collected before and during therapy, and at the time of progression, will be used to identify
changes in the malignant cells, TME and immune cell cohort associated with, and potentially predictive of,
therapeutic response and drug resistance. Aim 5.4 will analyze the effects of ICIs on skin-resident T-cells and
compare adverse responses to the idiopathic conditions they resemble; analysis of local responses to retinoids
and steroids will provide new insight into immune homeostasis in the skin. Aim 5.5 will identify features
associated with (and ultimately predictive of) exceptional response to ICIs in brain tumors and provide data on
biomarkers that can be evaluated in Bayesian adaptive clinical trials. Aim 5.6 will investigate the connection
between immune infiltration and intrinsic or drug-induced genomic instability in triple negative breast cancers
(TNBC). Aim 5.7 will integrate data on tumor phenotypes, drug interventions and clinical responses using a
range of supervised and unsupervised machine-learning methods, including methods based on network priors,
and also link scRNA transcriptomics with t-CycIF image data using a multi-view learning framework.
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会议论文
Defining regulators of immunity to acute infection using CRISPR screens
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批准号:10210502
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项目类别:
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资助金额:$10.99万
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财政年份:2020
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负责人:Arlene H. Sharpe
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依托单位:
Abbreviated targeted therapy to improve anti-PD-1 inhibitor efficacy in melanoma
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批准号:10153453
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项目类别:
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资助金额:$38.06万
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财政年份:2018
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负责人:Arlene H. Sharpe
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依托单位:
Abbreviated targeted therapy to improve anti-PD-1 inhibitor efficacy in melanoma
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批准号:9906872
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项目类别:
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资助金额:$38.05万
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财政年份:2018
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负责人:Arlene H. Sharpe
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依托单位:
Abbreviated targeted therapy to improve anti-PD-1 inhibitor efficacy in melanoma
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批准号:9576657
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项目类别:
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资助金额:$39.83万
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财政年份:2018
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负责人:Arlene H. Sharpe
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依托单位:
Defining regulators of immunity to acute infection using CRISPR screens
-
批准号:10207344
-
项目类别:
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资助金额:$229.25万
-
财政年份:2017
-
负责人:Arlene H. Sharpe
-
依托单位:
Project 1: CRISPR screens to discover regulators of CD8 and CD4 cell fates and function
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批准号:10207349
-
项目类别:
-
资助金额:$86.54万
-
财政年份:2017
-
负责人:Arlene H. Sharpe
-
依托单位:
Defining regulators of immunity to acute infection using CRISPR screens
-
批准号:9380804
-
项目类别:
-
资助金额:$246.29万
-
财政年份:2017
-
负责人:Arlene H. Sharpe
-
依托单位:
Core D: Mouse Perturbation Core
-
批准号:10207348
-
项目类别:
-
资助金额:$81.28万
-
财政年份:2017
-
负责人:Arlene H. Sharpe
-
依托单位:
Administrative Core
-
批准号:10207345
-
项目类别:
-
资助金额:$37.75万
-
财政年份:2017
-
负责人:Arlene H. Sharpe
-
依托单位:
Defining regulators of immunity to acute infection using CRISPR screens
-
批准号:10266219
-
项目类别:
-
资助金额:$10.99万
-
财政年份:2017
-
负责人:Arlene H. Sharpe
-
依托单位:
T Cell Costimulatory Pathways: Function and Interactions
-
批准号:9121451
-
项目类别:
-
资助金额:$3.96万
-
财政年份:2016
-
负责人:Arlene H. Sharpe
-
依托单位:
Project 1: Costimulation and Regulation of Anti-viral Immunity
-
批准号:9121455
-
项目类别:
-
资助金额:$53.35万
-
财政年份:2016
-
负责人:Arlene H. Sharpe
-
依托单位:
Project 1 - Modulation of Tolerance and Autoimmunity by Inhibitory Receptors
-
批准号:10023668
-
项目类别:
-
资助金额:$47.04万
-
财政年份:2015
-
负责人:Arlene H. Sharpe
-
依托单位:
Project 1 - Modulation of Tolerance and Autoimmunity by Inhibitory Receptors
-
批准号:10239110
-
项目类别:
-
资助金额:$45.63万
-
财政年份:2015
-
负责人:Arlene H. Sharpe
-
依托单位:
Modulation of Tolerance and Autoimmunity by Inhibitory Receptors
-
批准号:8854452
-
项目类别:
-
资助金额:$58.7万
-
财政年份:2015
-
负责人:Arlene H. Sharpe
-
依托单位:
Project 1 - Modulation of Tolerance and Autoimmunity by Inhibitory Receptors
-
批准号:10670295
-
项目类别:
-
资助金额:$45.63万
-
财政年份:2015
-
负责人:Arlene H. Sharpe
-
依托单位:
Project 1 - Modulation of Tolerance and Autoimmunity by Inhibitory Receptors
-
批准号:10663576
-
项目类别:
-
资助金额:$45.63万
-
财政年份:2015
-
负责人:Arlene H. Sharpe
-
依托单位:
Role of Costimulation in Control of the Effector and Regulatory T Cell Balance
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批准号:8289441
-
项目类别:
-
资助金额:$62.9万
-
财政年份:2011
-
负责人:Arlene H. Sharpe
-
依托单位:
Role of Immune Regulatory Pathways in BRAF Targeted Therapy In Melanoma
-
批准号:8555326
-
项目类别:
-
资助金额:$24.84万
-
财政年份:2011
-
负责人:Arlene H. Sharpe
-
依托单位:
Regulation of chronic viral infection by co-inhibitory pathways
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批准号:8432766
-
项目类别:
-
资助金额:$12.68万
-
财政年份:2010
-
负责人:Arlene H. Sharpe
-
依托单位:
海外基金