The role of TIM3 and CEACAM1 in anti-tumor function of human effector T cells

TIM3和CEACAM1在人效应T细胞抗肿瘤功能中的作用

基本信息

  • 批准号:
    10215429
  • 负责人:
  • 金额:
    $ 36.83万
  • 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:
    2017-09-01 至 2023-07-31
  • 项目状态:
    已结题

项目摘要

Solid tumors of the thorax continue to be a significant healthcare burden. Lung cancer remains the leading cause of cancer death. Malignant pleural mesothelioma (MPM) is still without cure and portends a dismal prognosis of about one year. One promising immunotherapeutic approach has been checkpoint blockade of inhibitory receptors (IRs), like programmed death 1 (PD1). However, response to PD1 checkpoint blockade is seen only in 20% of patients with solid tumors. Genetic modification of T cells (with chimeric antigen receptors (CARs) and transgenic T cell receptors (TCRs)) does not prevent the hypofunction induced by PD1, supporting the need to better understand the way IRs interact with the TME and the way they signal within T cells to induce TIL hypofunction—in both naturally occurring tumor infiltrating lymphocytes (TILs) and adoptively transferred, genetically engineered TILs. We previously showed that PD1 checkpoint blockade in xenograft models of lung cancer and MPM is able to augment the control of flank tumor growth after one intravenous dose of tumor-reactive human effector T cells. However, the augmentation is modest and tumors continue to progress. Upon closer analysis of the TILs isolated from the flank tumors of the mice, we made a few observations that helped us understand why the TILs were still suppressed in their anti-tumor function: 1) PD1 blockade was able to only partially preserve TIL function, 2) TILs had multiple IRs, other than PD1 upregulated, 3) some of these IRs seemed to increase in expression in response to PD1 blockade. One IR that was upregulated in the TILs, particularly in the TILs from the mice that also received PD1 blockade, was TIM3. When we subsequently treated flank tumor bearing mice that were given one adoptive transfer of T cells intravenously with repeated intraperitoneal doses of anti-TIM3 antibody, a very minor effect was seen. This may be due to a second receptor, CEACAM1, that has been shown to regulate the function of TIM3 on murine T cells. Flow cytometric analysis of our own human T cells revealed the presence of four difference populations: 1) TIM3-/CEACAM1-, 2) TIM3+/CEACAM1-, 3) TIM3-/CEACAM1+, and 4) TIM3+/CEACAM1+. We presumed that the anti-TIM3 antibody interfered with not only the inhibitory TIM3 (i.e. that which was coexpressed with CEACAM1 in population #4) but also interfered with the activating TIM3 (i.e. that which had no CEACAM1 coexpression in population #2), hence resulting in a net minimal effect on T cell control of tumor growth. CEACAM1 is also expressed on our tumor cells. In light of TIM3 being a promising target in cancer immunotherapy, this proposal aims to clarify its function as well as its interplay with CEACAM1. We propose to investigate the most important ligands for TIM3 (Aim 1), the impact of TIM3’s extracellular ligand-recognition domain vs. TIM3’s intracellular signaling domains on TIM3-induced T cell hypofunction (Aim 2), the impact of CEACAM1 on the anti-tumor activity of human effector T cells (Aim 3).
胸部实体瘤仍然是一个重大的医疗负担。肺癌仍然是 癌症死亡的原因。恶性胸膜间皮瘤(MPM)仍然没有治愈,预示着一个令人沮丧的 一年左右的预后。一种有前途的免疫方法是检查点阻断。 抑制性受体(IR),如程序性死亡1(PD 1)。然而,对PD 1检查点封锁的反应是 仅见于20%的实体瘤患者。T细胞的遗传修饰(用嵌合抗原受体 (汽车)和转基因T细胞受体(TCR))不能预防由PD 1诱导的功能减退,支持了 需要更好地了解IR与TME相互作用的方式以及它们在T细胞内发出信号的方式, 诱导TIL功能低下-在天然存在肿瘤浸润淋巴细胞(TIL)和过继性TIL中 转基因的TIL我们之前的研究表明,PD 1检查点阻断在异种移植中, 肺癌模型和MPM能够在一次静脉注射后增强对侧腹肿瘤生长的控制 剂量的肿瘤反应性人效应T细胞。然而,增加是适度的,肿瘤继续 中求进工作总在对从小鼠的侧腹肿瘤分离的TIL进行更仔细的分析后,我们制备了几个 这些观察有助于我们理解为什么TILs的抗肿瘤功能仍然受到抑制:1)PD 1 阻断只能部分保留TIL功能,2)除了PD 1上调外,TIL具有多种IR, 3)这些IR中的一些似乎响应于PD 1阻断而表达增加。一个IR是 在TIL中,特别是在来自也接受PD 1阻断的小鼠的TIL中,上调的是TIM 3。 当我们随后治疗接受了一次过继性T细胞转移的侧腹荷瘤小鼠时, 静脉内给予重复腹膜内剂量的抗TIM 3抗体,观察到非常小的作用。这 这可能是由于第二种受体CEACAM 1,它已被证明可以调节小鼠细胞上TIM 3的功能。 T细胞。对我们自己的人类T细胞的流式细胞术分析揭示了四种差异的存在。 群体:1)TIM 3-/CEACAM 1-,2)TIM 3 +/CEACAM 1-,3)TIM 3-/CEACAM 1+,和4)TIM 3 +/CEACAM 1+。 我们推测抗TIM 3抗体不仅干扰抑制性TIM 3(即, 与群体#4中的CEACAM 1共表达),但也干扰活化性TIM 3(即, 在群体#2中没有CEACAM 1共表达),因此导致对肿瘤的T细胞控制的净最小效应 增长CEACAM 1也在我们的肿瘤细胞上表达。鉴于TIM 3是癌症中有希望的靶点, 免疫疗法,该提案旨在阐明其功能以及其与CEACAM 1的相互作用。我们建议 研究TIM 3最重要的配体(目的1),TIM 3的细胞外配体识别的影响 结构域与TIM 3的细胞内信号传导结构域对TIM 3诱导的T细胞功能减退的影响(目的2), CEACAM 1对人效应T细胞的抗肿瘤活性的影响(目的3)。

项目成果

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Steven Mark Albelda其他文献

Steven Mark Albelda的其他文献

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{{ truncateString('Steven Mark Albelda', 18)}}的其他基金

Project 2 - Preclinical studies: Overcoming tumor heterogeneity
项目2 - 临床前研究:克服肿瘤异质性
  • 批准号:
    10241978
  • 财政年份:
    2018
  • 资助金额:
    $ 36.83万
  • 项目类别:
Project 2 - Preclinical studies: Overcoming tumor heterogeneity
项目2 - 临床前研究:克服肿瘤异质性
  • 批准号:
    10006192
  • 财政年份:
    2018
  • 资助金额:
    $ 36.83万
  • 项目类别:
Core A - Administrative Core
核心 A - 行政核心
  • 批准号:
    10241980
  • 财政年份:
    2018
  • 资助金额:
    $ 36.83万
  • 项目类别:
Extending Chimeric Antigen (CAR) T cell therapy to thoracic cancers
将嵌合抗原 (CAR) T 细胞疗法扩展到胸部癌症
  • 批准号:
    10006051
  • 财政年份:
    2018
  • 资助金额:
    $ 36.83万
  • 项目类别:
Extending Chimeric Antigen (CAR) T cell therapy to thoracic cancers
将嵌合抗原 (CAR) T 细胞疗法扩展到胸部癌症
  • 批准号:
    10241975
  • 财政年份:
    2018
  • 资助金额:
    $ 36.83万
  • 项目类别:
Core A - Administrative Core
核心 A - 行政核心
  • 批准号:
    10006194
  • 财政年份:
    2018
  • 资助金额:
    $ 36.83万
  • 项目类别:
Use of Genetically Engineered T cells Targeting Tumor Stroma to Treat Lung Cancer
使用靶向肿瘤基质的基因工程 T 细胞治疗肺癌
  • 批准号:
    8578578
  • 财政年份:
    2013
  • 资助金额:
    $ 36.83万
  • 项目类别:
Use of Genetically Engineered T cells Targeting Tumor Stroma to Treat Lung Cancer
使用靶向肿瘤基质的基因工程 T 细胞治疗肺癌
  • 批准号:
    9101792
  • 财政年份:
    2013
  • 资助金额:
    $ 36.83万
  • 项目类别:
Use of Genetically Engineered T cells Targeting Tumor Stroma to Treat Lung Cancer
使用靶向肿瘤基质的基因工程 T 细胞治疗肺癌
  • 批准号:
    8739623
  • 财政年份:
    2013
  • 资助金额:
    $ 36.83万
  • 项目类别:
Genetic Influence on Incidence of Acute Lung Injury
遗传对急性肺损伤发生率的影响
  • 批准号:
    7796690
  • 财政年份:
    2009
  • 资助金额:
    $ 36.83万
  • 项目类别:

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