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

• 批准号: 10648618
• 负责人: Stefani Spranger
• 金额: $ 47.66万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/10648618
• 关键词: Address; Affect; CD8-Positive T-Lymphocytes; CD80 gene; CD86 gene; CXCR3 gene; Cancer Patient; Cell physiology; Cells; Chronic; Clinical; Clinical Data; Communicable Diseases; Cross Presentation; Data; Dendritic Cells; Dendritic cell activation; Development; Disease; Environmental Impact; Epigenetic Process; Exposure to; Functional disorder; Generations; Grant; Immune; Immune Evasion; Immune response; Immunity; Immunologics; Immunosuppression; Immunotherapy; Impairment; Infiltration; Interleukin-12; K-ras mouse model; KRAS oncogenesis; KRAS2 gene; Knowledge; Lung; Lung Adenocarcinoma; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Mediastinal; Mediastinal lymph node group; Mediating; Minority; Modeling; Molecular; Mutation; Non-Small-Cell Lung Carcinoma; Organ; Patients; Phenotype; Population; Production; Refractory; Regulatory T-Lymphocyte; Reporting; Resistance; Role; STK11 gene; Site; Structure of parenchyma of lung; T cell differentiation; T cell infiltration; T cell regulation; T cell response; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; T-cell inflamed; TP53 gene; Testing; Therapeutic Agents; Therapeutic Intervention; Time; Tissues; Translating; Tumor Antigens; Tumor Immunity; Up-Regulation; Virus Diseases; Work; anti-PD-1; anti-tumor immune response; cancer immunotherapy; cancer therapy; cancer type; clinical practice; clinical predictors; draining lymph node; effector T cell; exhaust; exhaustion; experience; immune checkpoint blockade; immune modulating agents; immunoregulation; imprint; insight; melanoma; mouse model; neoplastic cell; novel; pre-clinical; prevent; programmed cell death protein 1; programs; receptor; resistance mechanism; response; restraint; tumor; tumor eradication; tumor-immune system interactions

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 癌症免疫疗法是最重要的检查点阻滞疗法（CBT），彻底改变了 癌症治疗。但是，迄今为止，只有少数癌症患者正在经历长期的临床益处， 虽然大多数患者在初步反应后没有反应或进展。那远，缺乏渗透 肿瘤反应性T细胞是对CBT缺乏敏感性（例如抗PD-1）的高度相关标记。 但是，肿瘤反应性T细胞浸润的反面结论将可以预测抗肿瘤 免疫反应并不总是站起来。仅在非小细胞肺癌（NSCLC）的患者中 一半患有可检测的肿瘤反应性T细胞浸润的患者对CBT有反应。特别是由NSCLC驱动的 与p53损失结合的致癌性KRAS突变经常对CBT难治性。这个观察结果 提出了一个关键问题，即在T细胞中介导对CBT的抗性的其他机制 NSCLC子集，以及其他可能的其他癌症类型。此外，它增加了抗肿瘤免疫的可能性 反应可能主要受到器官特定的免疫微环境的影响。特别是 解决这个概念，我们已经建立了KRAS/p53驱动的肺腺癌的小鼠模型，即 对CBT有抗性，但同时显示出效应子CD8+ T细胞的浸润。我们的数据表明，需求 高度的T细胞浸润CD8+ T细胞浸润肺部肿瘤本质上是功能失调，渲染 T细胞反应无法消除肿瘤细胞。发现这些差异独立于 肿瘤特异性抗原，并在T细胞激活肺部排出肺部肿瘤膜中的印迹 淋巴结。此外，观察到的肺肿瘤特异性T细胞功能障碍与常规 T细胞耗尽表型通常被描述为PD1+，LAG3+，TIM3+，对CBT治疗高度敏感。基于 关于这些观察结果，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 T细胞活化状态，在纵隔淋巴结启动过程中由肺衍生的树突状细胞诱导 并以抗肿瘤效应函数受损为特征。通过确定免疫学基础 负责观察到的T细胞功能障碍（AIM 1）和树突状细胞的刺激能力（AIM 2）， 我们将能够阐明介导T中免疫爆发的未被发现的免疫抑制机制 细胞增添肿瘤。通过更好地了解如何诱导肺部限制抗肿瘤免疫力 促进新型免疫疗法的发展。虽然这笔赠款将重点放在肺癌上，但可以想象 任何确定的机制都更广泛地适用。最终的前提将永远是增加 具有持久抗肿瘤免疫反应和长期耐用临床益处的患者数量。