Identifying the role of Ntrk1 in immunosuppression in Kras/p53 mutant lung cancer

鉴定 Ntrk1 在 Kras/p53 突变肺癌免疫抑制中的作用

基本信息

  • 批准号:
    9906415
  • 负责人:
  • 金额:
    $ 7.01万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-12-09 至 2022-12-08
  • 项目状态:
    已结题

项目摘要

Project Summary Lung cancer is the leading cause of cancer-related deaths in the United States, and the 5-year survival rate of all lung cancer patients combined is only about 18%. The implementation of cancer immunotherapeutics for solid tumors such as lung cancers has shown great promise and provided the possibility for improved outcome in a small percentage of patients. However, the majority of patients show little to no response or acquire resistance during treatment with checkpoint inhibitors delivered as a monotherapy. Therefore, identifying resistance mechanisms and potential combination therapy approaches is a critical need to improve response rates to immune checkpoint inhibitors and patient prognosis. To address this, a clinically relevant in vivo shRNA dropout screen focused on genes encoding for FDA-approved drug targets (FDAome) was performed in epithelial and mesenchymal Kras/p53 (KP) mutant murine lung cancer cells. Mice were then treated with either isotype or anti- PD-1 antibody. Sequencing for the barcoded shRNAs revealed that Ntrk1 was significantly depleted from mesenchymal tumors challenged with PD-1 blockade compared to isotype treated tumors, suggesting it provides a survival advantage to these tumor cells when under immune system pressure. Preliminary data confirmed Ntrk1 transcript levels are upregulated in mesenchymal tumors treated with PD-1 inhibitors and cell lines derived from resistant tumors, and analysis of human NSCLC cell lines revealed that Ntrk1 mRNA levels correlate with a more aggressive, mesenchymal cell phenotype. Additionally, Ntrk1 overexpressing cells upregulate PD-L1 expression when co-cultured with splenocytes through upregulation of JAK signaling. Stable knockdown of Ntrk1 in mesenchymal murine KP mutant lung cancer cells reduced tumor growth in vivo and analysis of tumor- infiltrating T cell populations via flow cytometry showed that CD8+ T cell exhaustion was significantly reduced, whereas overexpression of Ntrk1 promoted CD8+ T cell exhaustion, thus decreasing effector status. These tumors also have an altered microenvironment, with upregulation of classically immunosuppressive cytokines such as IL-10. PD-1 protein levels were also significantly increased in Ntrk1-high human NSCLC cell lines, providing additional evidence that Ntrk1 may be a modulator of immune system functionality in human lung disease. The central hypothesis of the proposed work is that Ntrk1 upregulation causes acquired resistance to PD-1 blockade via aberrant JAK signaling and downstream CD8+ T cell dysfunction, thereby promoting tumor cell survival. A variety of powerful tools will be utilized to test this hypothesis, including time-lapse imaging of dynamic T cell-tumor cell interactions, genetically-engineered and syngeneic preclinical models of lung cancer to analyze immune subpopulations as a function of Ntrk1 expression, and IHC analyses of human NSCLC tissue samples. The goal of the proposed work is to provide strong evidence for a rational drug combination of Ntrk1 inhibitors with PD-1 blockade to be carried forward into the clinic to abrogate immune checkpoint blockade resistance and ultimately improve patient outcomes.
项目摘要 肺癌是美国癌症相关死亡的主要原因, 所有肺癌患者加起来只有大约18%。癌症免疫治疗的实施对于固体 肿瘤如肺癌已经显示出很大的希望,并提供了改善预后的可能性, 小部分患者。然而,大多数患者几乎没有反应或获得耐药性 在作为单一疗法递送的检查点抑制剂治疗期间。因此,鉴定耐药性 机制和潜在的联合治疗方法是一个关键的需要,以提高反应率, 免疫检查点抑制剂和患者预后。为了解决这个问题,临床相关的体内shRNA缺失 在上皮细胞中进行集中于编码FDA批准的药物靶点(FDAome)的基因的筛选, 间充质Kras/p53(KP)突变小鼠肺癌细胞。然后用同种型或抗- PD-1抗体。对条形码化的shRNA进行测序显示,Ntrk 1从 与同种型治疗的肿瘤相比,用PD-1阻断剂攻击的间充质肿瘤,表明它提供了 在免疫系统压力下,这些肿瘤细胞的生存优势。初步数据证实 在用PD-1抑制剂处理的间充质肿瘤中Ntrk 1转录水平上调, 对人NSCLC细胞系的分析显示,Ntrk 1 mRNA水平与 更具侵略性的间充质细胞表型此外,Ntrk 1过表达细胞上调PD-L1 当与脾细胞共培养时,通过上调JAK信号传导表达。Ntrk 1的稳定敲除 在间充质鼠KP突变肺癌细胞中减少体内肿瘤生长和分析肿瘤- 通过流式细胞术的浸润T细胞群显示CD 8 + T细胞耗竭显著降低, 而Ntrk 1的过表达促进CD 8 + T细胞耗竭,从而降低效应子状态。这些 肿瘤还具有改变的微环境,具有经典免疫抑制细胞因子的上调 例如IL-10。PD-1蛋白水平在Ntrk 1高人NSCLC细胞系中也显著增加, 提供了Ntrk 1可能是人肺中免疫系统功能的调节剂的额外证据 疾病拟议工作的中心假设是Ntrk 1上调导致对抗结核病的获得性抵抗。 通过异常JAK信号传导和下游CD 8 + T细胞功能障碍阻断PD-1,从而促进肿瘤 细胞存活各种强大的工具将被用来测试这一假设,包括时间推移成像的 动态T细胞-肿瘤细胞相互作用、肺癌的基因工程和同基因临床前模型 分析作为Ntrk 1表达函数的免疫亚群,以及人NSCLC组织的IHC分析 样品这项工作的目的是为Ntrk 1的合理药物组合提供强有力的证据。 将PD-1阻断剂用于临床,以消除免疫检查点阻断 并最终改善患者的预后。

项目成果

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Jessica Konen其他文献

Jessica Konen的其他文献

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{{ truncateString('Jessica Konen', 18)}}的其他基金

Identifying the role of Ntrk1 in immunosuppression in Kras/p53 mutant lung cancer
鉴定 Ntrk1 在 Kras/p53 突变肺癌免疫抑制中的作用
  • 批准号:
    10304891
  • 财政年份:
    2019
  • 资助金额:
    $ 7.01万
  • 项目类别:
Defining an LKB1-regulated motility switch in cancer cell invasion and metastasis
定义癌细胞侵袭和转移中 LKB1 调节的运动开关
  • 批准号:
    8717302
  • 财政年份:
    2014
  • 资助金额:
    $ 7.01万
  • 项目类别:
Defining an LKB1-regulated motility switch in cancer cell invasion and metastasis
定义癌细胞侵袭和转移中 LKB1 调节的运动开关
  • 批准号:
    9064098
  • 财政年份:
    2014
  • 资助金额:
    $ 7.01万
  • 项目类别:
Defining an LKB1-regulated motility switch in cancer cell invasion and metastasis
定义癌细胞侵袭和转移中 LKB1 调节的运动开关
  • 批准号:
    8892799
  • 财政年份:
    2014
  • 资助金额:
    $ 7.01万
  • 项目类别:

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