(PQ#3) Novel tumor intrinsic PD-L1 signals direct tumor immune cell infiltration
(PQ
基本信息
- 批准号:9926828
- 负责人:
- 金额:$ 64.05万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-06-01 至 2022-05-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAutologousCell ProliferationCell surfaceCellsCellular biologyClinicalClustered Regularly Interspaced Short Palindromic RepeatsComplementCytoplasmDataDefectEngineeringFDA approvedFRAP1 geneFundingGenesGrowthHumanImmuneImmune responseImmunologyImmunotherapyIn VitroInfiltrationInflammatory InfiltrateJointsKnock-outKnowledgeLeadMalignant NeoplasmsMalignant neoplasm of urinary bladderMediatingMelanoma CellModalityModelingMolecular MedicineMusMutateMutationOutcomePD-1/PD-L1Pathway interactionsPatient-Focused OutcomesPatientsPharmacotherapyPositioning AttributePre-Clinical ModelPrediction of Response to TherapyPublicationsReagentRegulationResearchResearch PersonnelResistanceSignal TransductionSiteSkin graftStudy modelsSurfaceT-LymphocyteTestingTransplantationTreatment outcomeTumor Cell LineTumor EscapeTumor ImmunityTumor-infiltrating immune cellsValidationanti-PD-1anti-PD-L1anti-PD-L1 antibodiesbasecancer therapychemokineclinical translationfollow-uphuman tissuehumanized mouseimmune clearanceimprovedin vivoinhibitor/antagonistinsightknock-downmTOR Inhibitormelanomamouse modelneoplasm immunotherapyneoplastic cellnovelnovel markerpredicting responseprogrammed cell death ligand 1programmed cell death protein 1responsesmall hairpin RNAsuccesstraffickingtranscriptome sequencingtreatment effecttreatment responsetumortumor growthtumor immunologytumor microenvironmenttumor progressionvector
项目摘要
We respond to PQ3 with our data showing that tumor PD-L1 (CD274, B7-H1) is a major regulator of tumor
inflammatory infiltrates. Our preliminary data show that melanoma PD-L1 regulates TIL through several
previously unknown tumor-intrinsic and extrinsic mechanisms. We define novel effects of tumor intrinsic PD-L1
signaling on tumor proliferation, sensitivity to immune killing, in vivo growth independent of anti-tumor
immunity, and regulation of mTOR signals. We identified intracellular PD-L1, including those whose surface
expression is low or negative, and identified interactions with tumor PD-1. We hypothesize that melanoma
intrinsic PD-L1-driven signals, particularly mTOR signals, alter tumor progression and treatment
responses. The research team is comprised of tumor immunotherapy, tumor immunology and PD-L1 experts
at UTHSCSA and Dartmouth. We focus on melanoma for scientific reasons and based on our expertise.
Aim 1 Define how tumor PD-L1 alters tumor immune infiltrates and immunotherapy responses. We use
control versus PD-L1lo (shRNA) B16 in a novel model to study differential treatment outcomes by tumor PD-L1
status. We generated PD-L1KO B16 by CRISPR for highly detailed follow up mechanistic studies, and to assess
if PD-L1 null status differentially affects treatment versus PD-L1lo. Effects will also be tested in transplanted
BrafV600E mutated D4M melanoma (PD-L1+) engineered to be PD-L1lo and PD-L1KO, in mice with induced
BrafV600E melanomas, and in syngeneic skin grafts of skin from Braf/Pten versus PD-L1KO Braf/Pten mice.
Aim 2 Test tumor PD-L1-driven mTOR signal effects on TIL and immunotherapy responses. We will test
PD-L1 KO, PD-1 KO and double KO melanoma cells for mTOR signals, TIL and treatment effects. Cells will be
engineered for defects in mTORC1/2 for mechanistic studies, complemented with mTOR inhibitor treatments.
We will use engineered tumors that express cytoplasm-only versus cell surface-only PD-L1, to define novel,
intracellular PD-L1 signals. Constructs with mutations in known PD-1 signal sites will be engineered into these
tumors for a complete understanding of PD-L1/PD-1 interactions.
Aim 3 Define cell-intrinsic PD-L1 effects in human melanoma. We use well-defined human melanoma lines
that are basal PD-L1+ and/or PD-1+ and/or BrafV600E mutated. We will use human vectors to knock down or
knock out PD-L1, PD-1 and mTORC1/2 genes. In vitro assessments of effects on proliferation, responses to
mTOR inhibitors, αPD-L1 and αPD-1 will be assessed. In vivo effects in NSG mice will be assessed. Primary
human melanoma lines will be studied to complement data from long-term lines.
我们的数据显示肿瘤PD-L1 (CD274, B7-H1)是肿瘤的主要调节因子
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Tyler J. Curiel其他文献
ESTABLISHMENT OF A DOUBLE-HUMANIZED MOUSE MODEL USING PATIENT-DERIVED XENOGRAFT BLADDER CANCER TUMOR CELL LINE AND HUMAN γδ T-CELLS
- DOI:
10.1016/j.urolonc.2024.01.171 - 发表时间:
2024-03-01 - 期刊:
- 影响因子:
- 作者:
Shaun Trecarten;Robert S. Svatek;Niannian Ji;Zhen-Ju Shu;Tyler J. Curiel;Neelam Mukherjee;Jamie Furman - 通讯作者:
Jamie Furman
PD48-06 2 YEAR CLINICAL AND IMMUNOLOGIC OUTCOMES OF INTRADERMAL BCG PRIMING PRIOR TO INTRAVESICAL INDUCTION IMMUNOTHERAPY FOR HIGH RISK NON-MUSCLE INVASIVE BLADDER CANCER
- DOI:
10.1016/j.juro.2017.02.2354 - 发表时间:
2017-04-01 - 期刊:
- 影响因子:
- 作者:
Niannan Ji;Edwin E. Morales;Neelam Mukherjee;Vincent Hurez;Tyler J. Curiel;Getahun Abate;Daniel F. Hoft;Robert S. Svatek - 通讯作者:
Robert S. Svatek
60: Oral rapamycin prevents carcinogen-induced dermal carcinogenesis through immune mechanisms
- DOI:
10.1016/j.cyto.2013.06.063 - 发表时间:
2013-09-01 - 期刊:
- 影响因子:
- 作者:
Vinh Dao;Vincent Hurez;Sri Lakshmi Pandeswara;Lishi Sun;Aijie Liu;Paul Hasty;Dave Sharp;Tyler J. Curiel - 通讯作者:
Tyler J. Curiel
Tyler J. Curiel的其他文献
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{{ truncateString('Tyler J. Curiel', 18)}}的其他基金
Bladder cancer PD-L1 control of homologous recombination: Basic mechanisms applied to novel treatments
膀胱癌 PD-L1 对同源重组的控制:应用于新疗法的基本机制
- 批准号:
10467877 - 财政年份:2022
- 资助金额:
$ 64.05万 - 项目类别:
Bladder cancer PD-L1 control of homologous recombination: Basic mechanisms applied to novel treatments
膀胱癌 PD-L1 对同源重组的控制:应用于新疗法的基本机制
- 批准号:
10688261 - 财政年份:2022
- 资助金额:
$ 64.05万 - 项目类别:
Regulation of ER-beta Signaling in Carcinogenesis
ER-β 信号传导在癌发生过程中的调节
- 批准号:
10092967 - 财政年份:2019
- 资助金额:
$ 64.05万 - 项目类别:
(PQ2) PD-L1/PD-1 signals in aged hosts undergoing cancer immunotherapy
(PQ2) 接受癌症免疫治疗的老年宿主体内的 PD-L1/PD-1 信号
- 批准号:
9788318 - 财政年份:2018
- 资助金额:
$ 64.05万 - 项目类别:
(PQ2) PD-L1/PD-1 signals in aged hosts undergoing cancer immunotherapy
(PQ2) 接受癌症免疫治疗的老年宿主体内的 PD-L1/PD-1 信号
- 批准号:
10381324 - 财政年份:2018
- 资助金额:
$ 64.05万 - 项目类别:
(PQ2) PD-L1/PD-1 signals in aged hosts undergoing cancer immunotherapy
(PQ2) 接受癌症免疫治疗的老年宿主体内的 PD-L1/PD-1 信号
- 批准号:
10475260 - 财政年份:2018
- 资助金额:
$ 64.05万 - 项目类别:
(PQ2) PD-L1/PD-1 signals in aged hosts undergoing cancer immunotherapy
(PQ2) 接受癌症免疫治疗的老年宿主体内的 PD-L1/PD-1 信号
- 批准号:
10247570 - 财政年份:2018
- 资助金额:
$ 64.05万 - 项目类别:
(PQ#3) Novel tumor intrinsic PD-L1 signals direct tumor immune cell infiltration
(PQ
- 批准号:
9307468 - 财政年份:2017
- 资助金额:
$ 64.05万 - 项目类别:
Immune aspects of mTOR inhibition for cancer prevention (PQ5)
mTOR 抑制的免疫方面预防癌症 (PQ5)
- 批准号:
8538910 - 财政年份:2012
- 资助金额:
$ 64.05万 - 项目类别:
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