(PQ#3) Novel tumor intrinsic PD-L1 signals direct tumor immune cell infiltration

(PQ

基本信息

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

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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
  • 批准号:
    9926828
  • 财政年份:
    2017
  • 资助金额:
    $ 65.08万
  • 项目类别:
SENIOR LEADERSHIP
高层领导
  • 批准号:
    8709459
  • 财政年份:
    2013
  • 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:

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