(PQ#3) Novel tumor intrinsic PD-L1 signals direct tumor immune cell infiltration
(PQ
基本信息
- 批准号:9307468
- 负责人:
- 金额:$ 65.08万
- 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:AffectAntibodiesAutologousCell ProliferationCell surfaceCellsCellular biologyClinicalClustered Regularly Interspaced Short Palindromic RepeatsComplementCytoplasmDataDefectEngineeringFDA approvedFRAP1 geneFundingGenesGrowthHumanImmuneImmune EvasionImmune responseImmunologyImmunotherapyIn VitroInfiltrationInflammatory InfiltrateJointsKnock-outKnowledgeLeadMalignant NeoplasmsMalignant neoplasm of urinary bladderMediatingMelanoma CellModalityModelingMolecular MedicineMusMutateMutationOutcomePDCD1LG1 genePathway interactionsPatient-Focused OutcomesPatientsPharmacotherapyPositioning AttributePre-Clinical ModelPublicationsReagentRegulationResearchResearch PersonnelResistanceSignal TransductionSiteSkin graftStudy modelsSurfaceT-LymphocyteTestingTransplantationTreatment outcomeTumor Cell LineTumor ImmunityValidationbasecancer therapychemokineclinical translationfollow-uphuman tissuehumanized mouseimmune clearanceimprovedin vivoinhibitor/antagonistinsightkillingsknock-downmTOR Inhibitormelanomamouse modelneoplasm immunotherapyneoplastic cellnovelnovel markerpredicting responsepredictive of treatment responseresponsesmall 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.
我们对PQ3的回应是,我们的数据表明,肿瘤PD-L1(CD274,B7-H1)是肿瘤的主要调节因子
炎性浸润物。我们的初步数据显示,黑色素瘤PD-L1通过几种
以前未知的肿瘤内在和外在机制。我们定义了肿瘤内源性PD-L1的新作用
肿瘤增殖信号、免疫杀伤敏感性、体内生长独立于抗肿瘤
免疫力和mTOR信号的调节。我们鉴定了细胞内的PD-L1,包括那些其表面
低表达或阴性,并发现与肿瘤PD-1相互作用。我们假设黑色素瘤
内源性PD-L1驱动信号,特别是mTOR信号,改变肿瘤进展和治疗
回应。研究团队由肿瘤免疫疗法、肿瘤免疫学和PD-L1专家组成
在UTHSCSA和达特茅斯。我们专注于黑色素瘤是出于科学原因,并基于我们的专业知识。
目的1明确肿瘤PD-L1如何改变肿瘤免疫浸润和免疫治疗反应。我们用
对照与PD-L1lo(ShRNA)B16在研究肿瘤PD-L1差异治疗结果的新模型中的作用
状态。我们由CRISPR生成PD-L1KO B16,用于非常详细的后续机制研究,并评估
如果PD-L1零状态与PD-L1L0相比,对治疗有不同的影响。效果也将在移植后进行测试
BRAFV600E突变的D4M黑色素瘤(PD-L1+)基因工程化为PD-L1LO和PD-L1KO,诱导小鼠
BRAFV600E黑色素瘤,以及BRAF/PTEN与PD-L1KO BRAF/PTEN小鼠的同基因皮肤移植。
目的2检测肿瘤PD-L1驱动的mTOR信号对TIL和免疫治疗反应的影响。我们将测试
PD-L1KO、PD-1KO及双KO黑色素瘤细胞用于mTOR信号、TIL及治疗效果。单元格将是
针对mTORC1/2中的缺陷进行机械研究,并辅以mTOR抑制剂治疗。
我们将使用仅表达细胞质的工程化肿瘤与仅表达细胞表面的PD-L1,来定义新的,
细胞内PD-L1信号。在已知PD-1信号位点有突变的构建物将被工程到这些
以全面了解PD-L1/PD-1相互作用。
目的3明确细胞内源性PD-L1在人黑色素瘤中的作用。我们使用定义明确的人类黑色素瘤株系
碱基Pd-L1+和/或Pd-1+和/或BRAFV600E突变。我们将使用人类媒介来击倒或
敲除PD-L1、PD-1和mTORC1/2基因。体外评估对增殖的影响,对
将评估MTOR抑制剂、αPD-L1和αPD-1。对NSG小鼠的体内效应将进行评估。主要
将对人类黑色素瘤株进行研究,以补充长期株系的数据。
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:
$ 65.08万 - 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:
$ 65.08万 - 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:
$ 65.08万 - 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:
$ 65.08万 - 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:
$ 65.08万 - 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:
$ 65.08万 - 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:
$ 65.08万 - 项目类别:
(PQ#3) Novel tumor intrinsic PD-L1 signals direct tumor immune cell infiltration
(PQ
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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:
$ 65.08万 - 项目类别:
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