(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.
我们回应PQ 3,我们的数据显示肿瘤PD-L1(CD 274,B7-H1)是肿瘤的主要调节因子,
炎性浸润我们的初步数据显示,黑色素瘤PD-L1通过几种途径调节TIL,
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的新效应,
对肿瘤增殖的信号传导、对免疫杀伤的敏感性、不依赖于抗肿瘤的体内生长
免疫和调节mTOR信号。我们鉴定了细胞内PD-L1,包括那些表面
表达是低的或阴性的,并且鉴定了与肿瘤PD-1的相互作用。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
应答研究团队由肿瘤免疫治疗、肿瘤免疫学和PD-L1专家组成
和达特茅斯的学生我们专注于黑色素瘤的科学原因和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。我们使用
在新模型中对照与PD-L1 lo(shRNA)B16,以研究肿瘤PD-L1的差异治疗结果
status.我们通过CRISPR产生PD-L1 KO B16,用于高度详细的后续机制研究,并评估
如果PD-L1无效状态与PD-L1 lo相比对治疗的影响不同。效果也将在移植
BrafV 600 E突变的D4 M黑色素瘤(PD-L1+)在诱导的小鼠中被工程化为PD-L1 lo和PD-L1 KO
BrafV 600 E黑色素瘤,以及Braf/Pten与PD-L1 KO Braf/Pten小鼠的同基因皮肤移植物。
目的2检测肿瘤PD-L1驱动的mTOR信号对TIL和免疫治疗应答的影响。我们将测试
PD-L1 KO、PD-1 KO和双KO黑色素瘤细胞的mTOR信号、TIL和治疗效果。细胞将被
针对mTOR 1/2的缺陷进行工程化,以进行机制研究,并辅以mTOR抑制剂治疗。
我们将使用仅表达细胞质与仅表达细胞表面的PD-L1的工程肿瘤来定义新的,
细胞内PD-L1信号。在已知的PD-1信号位点中具有突变的构建体将被工程化到这些细胞中。
PD-L1/PD-1相互作用的完整理解。
目的3明确PD-L1在人黑色素瘤中的细胞内源性作用。我们使用定义明确的人类黑色素瘤细胞系
基础PD-L1+和/或PD-1+和/或BrafV 600 E突变。我们将使用人类载体来击倒或
敲除PD-L1、PD-1和mTORC 1/2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。将评估NSG小鼠中的体内效应。初级
将研究人黑素瘤细胞系以补充来自长期细胞系的数据。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
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
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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
- 批准号:
9926828 - 财政年份:2017
- 资助金额:
$ 65.08万 - 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:
$ 65.08万 - 项目类别:
相似海外基金
University of Aberdeen and Vertebrate Antibodies Limited KTP 23_24 R1
阿伯丁大学和脊椎动物抗体有限公司 KTP 23_24 R1
- 批准号:
10073243 - 财政年份:2024
- 资助金额:
$ 65.08万 - 项目类别:
Knowledge Transfer Partnership
Role of Natural Antibodies and B1 cells in Fibroproliferative Lung Disease
天然抗体和 B1 细胞在纤维增生性肺病中的作用
- 批准号:
10752129 - 财政年份:2024
- 资助金额:
$ 65.08万 - 项目类别:
CAREER: Next-generation protease inhibitor discovery with chemically diversified antibodies
职业:利用化学多样化的抗体发现下一代蛋白酶抑制剂
- 批准号:
2339201 - 财政年份:2024
- 资助金额:
$ 65.08万 - 项目类别:
Continuing Grant
Isolation and characterisation of monoclonal antibodies for the treatment or prevention of antibiotic resistant Acinetobacter baumannii infections
用于治疗或预防抗生素耐药鲍曼不动杆菌感染的单克隆抗体的分离和表征
- 批准号:
MR/Y008693/1 - 财政年份:2024
- 资助金额:
$ 65.08万 - 项目类别:
Research Grant
Developing first-in-class aggregation-specific antibodies for a severe genetic neurological disease
开发针对严重遗传神经系统疾病的一流聚集特异性抗体
- 批准号:
10076445 - 财政年份:2023
- 资助金额:
$ 65.08万 - 项目类别:
Grant for R&D
Discovery of novel nodal antibodies in the central nervous system demyelinating diseases and elucidation of the mechanisms through an optic nerve demyelination model
发现中枢神经系统脱髓鞘疾病中的新型节点抗体并通过视神经脱髓鞘模型阐明其机制
- 批准号:
23K14783 - 财政年份:2023
- 资助金额:
$ 65.08万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Elucidation of the mechanisms controlling the physicochemical properties and functions of supercharged antibodies and development of their applications
阐明控制超电荷抗体的理化性质和功能的机制及其应用开发
- 批准号:
23KJ0394 - 财政年份:2023
- 资助金额:
$ 65.08万 - 项目类别:
Grant-in-Aid for JSPS Fellows
Role of antibodies in hepatitis E virus infection
抗体在戊型肝炎病毒感染中的作用
- 批准号:
10639161 - 财政年份:2023
- 资助金额:
$ 65.08万 - 项目类别:
Defining the protective or pathologic role of antibodies in Post-Ebola Syndrome
定义抗体在埃博拉后综合症中的保护或病理作用
- 批准号:
10752441 - 财政年份:2023
- 资助金额:
$ 65.08万 - 项目类别:
Human CMV monoclonal antibodies as therapeutics to inhibit virus infection and dissemination
人 CMV 单克隆抗体作为抑制病毒感染和传播的治疗药物
- 批准号:
10867639 - 财政年份:2023
- 资助金额:
$ 65.08万 - 项目类别:














{{item.name}}会员




