Understanding the induction of T cell dysfunction in the context of lung cancer

了解肺癌背景下 T 细胞功能障碍的诱导

基本信息

  • 批准号:
    10648618
  • 负责人:
  • 金额:
    $ 47.66万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-03-14 至 2028-02-29
  • 项目状态:
    未结题

项目摘要

Project Summary Cancer immunotherapy, foremost checkpoint blockade therapy (CBT), has revolutionized the landscape of cancer treatment. However, to date only a minority of cancer patients is experiencing a long-term clinical benefit, while the majority of patients does not respond or progresses upon initial response. Thus far, a lack of infiltration with tumor-reactive T cells is a highly correlative marker for the lack of sensitivity to CBT, such as anti-PD-1. However, the reverse conclusion that a tumor-reactive T cell infiltrate would be predictive for an anti-tumor immune response does not always stand its ground. In patients with non-small cell lung cancer (NSCLC) only half of the patients with a detectable tumor-reactive T cell infiltrate respond to CBT. Especially NSCLC driven by oncogenic KRAS mutations in combination with p53-loss are frequently refractory to CBT. This observation poses the critical question as to which additional mechanisms mediating resistance to CBT in T cell infiltrated NSCLC subsets, and potentially also other cancer types. Further, it raises the possibility that anti-tumor immune responses may be dominantly affected by the organs’ specific immune microenvironment. To specifically address this notion, we have established a mouse model of KRAS/p53-driven lung adenocarcinoma, that is resistant to CBT but at the same time shows infiltration with effector CD8+ T cells. Our data suggest, that despite a high degree of T cell infiltration the CD8+ T cells infiltrating lung tumors are intrinsically dysfunctional, rendering the T cell response incapable of eradicating tumor cells. These differences were found to be independent of the tumor-specific antigen and rather imprinted at the time of T cell activation in the lung tumor-draining mediastinal lymph node. Further, the lung tumor-specific T cell dysfunction observed is strikingly different to the conventional T cell exhaustion phenotype often described as PD1+, Lag3+, Tim3+, and highly sensitive to CBT therapy. Based on these observations it is our central hypothesis that lung-specific T cell dysfunction is a unique and persisting state of T cell activation, induced by lung-derived dendritic cells during priming in the mediastinal lymph node and characterized by impaired anti-tumor effector function. By determining the immunological underpinnings that are responsible for the observed T cell dysfunction (Aim 1) and stimulatory capacity of dendritic cells (Aim 2), we will be able to elucidate yet undiscovered immune suppression mechanisms mediating immune evasion in T cell-inflamed tumors. By better understanding how lung-restricted anti-tumor immunity is induced we will be able to facilitate the development of novel immunotherapies. While this grant will focus on lung cancer it is conceivable that any identified mechanisms are more broadly applicable. The ultimate premise will always be to increase the number of patients with a durable anti-tumor immune response and long-term, durable clinical benefits.
项目摘要 癌症免疫疗法,最重要的是检查点阻断疗法(CBT),已经彻底改变了 癌症治疗。然而,到目前为止,只有少数癌症患者正在经历长期的临床益处, 而大多数患者在最初的反应中没有反应或进展。到目前为止,缺乏渗透 肿瘤反应性T细胞是CBT缺乏敏感性的一个高度相关的标志物,如抗PD-1。 然而,相反的结论是,肿瘤反应性T细胞浸润将预测抗肿瘤 免疫反应并不总是站稳脚跟。仅用于非小细胞肺癌(NSCLC)患者 在可检测到肿瘤反应性T细胞浸润的患者中,有一半对CBT有反应。特别是由NSCLC驱动的 致癌的KRAS突变结合P53缺失对CBT常常是难治性的。这一观察结果 提出了一个关键问题,即哪些额外的机制介导了T细胞对CBT的耐药性 NSCLC亚型,以及潜在的其他癌症类型。此外,它增加了抗肿瘤免疫的可能性 反应可能主要受器官特定的免疫微环境的影响。明确地说 针对这一概念,我们建立了KRAS/P53驱动的小鼠肺腺癌模型,即 对CBT耐药,但同时可见CD8+T细胞浸润。我们的数据表明,尽管 高度T细胞浸润性CD8+T细胞浸润性肺肿瘤是固有的功能障碍,呈现 T细胞反应不能根除肿瘤细胞。这些差异被发现是独立于 肿瘤特异性抗原,在肺肿瘤引流纵隔T细胞活化时印迹 淋巴结节。此外,观察到的肺肿瘤特异性T细胞功能障碍与常规显著不同 T细胞耗竭表型常描述为PD1+、LAG3+、TIM3+,对CBT治疗高度敏感。基座 根据这些观察,我们的中心假设是肺特异性T细胞功能障碍是一种独特而持久的 肺来源树突状细胞在纵隔淋巴结预充过程中的T细胞活化状态 并以抗肿瘤效应功能受损为特征。通过确定免疫学基础, 对观察到的T细胞功能障碍(目标1)和树突状细胞的刺激能力(目标2)负责, 我们将能够阐明尚未发现的免疫抑制机制,介导T细胞的免疫逃避 细胞发炎的肿瘤。通过更好地了解肺限制性抗肿瘤免疫是如何诱导的,我们将能够 以促进新型免疫疗法的发展。虽然这笔赠款将主要用于肺癌,但可以想象的是 任何已确定的机制都更广泛地适用。最终的前提始终是增加 具有持久的抗肿瘤免疫反应和长期、持久的临床益处的患者数量。

项目成果

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