Cachexia-mediated FcRn Modulation and Its Impact on Anti-PD1 Therapy in Lung Cancer

恶病质介导的 FcRn 调节及其对肺癌抗 PD1 治疗的影响

基本信息

批准号：
10678879
负责人：
Christopher C. Coss
金额：
$ 61.54万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-08 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10678879
关键词：
Affect Albumins Animal Model Antitumor Response Biological Markers Body Weight decreased Bone Marrow Bone Marrow Cells CTLA4 gene Cachexia Cancer Etiology Cancer Patient Catabolism Cells Cessation of life Clinical Clinical Pharmacology Clinical Trials Colon Carcinoma Combined Modality Therapy Data Dendritic Cells Homeostasis Hypoalbuminemia IgG1 IgG4 Immune Immune Evasion Immune checkpoint inhibitor Immune system Immunoglobulin G Immunologic Surveillance Immunosuppression Laboratories Link Liver Macrophage Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of pancreas Mediating Mediator Methods Monoclonal Antibodies Mus Myelogenous Myeloid Cells Non-Small-Cell Lung Carcinoma Organ Outcome Patient Selection Patients Phenotype Play Population Probability Proteins Public Health Publishing Recycling Research Resistance Role Selection for Treatments Serum Signal Transduction T-cell receptor repertoire Testing Therapeutic Tissues Tumor Immunity United States Variant advanced disease anti-PD1 therapy anti-tumor immune response antigen processing biomarker selection cancer cachexia cancer cell checkpoint therapy cytokine improved in vivo evaluation melanoma monocyte mortality mouse model neonatal Fc receptor neoplastic cell pembrolizumab programmed cell death ligand 1 programmed cell death protein 1 receptor response standard of care therapeutic target therapy resistant treatment response tumor

项目摘要

Summary The therapeutic targeting of cancer cells’ ability to evade immune surveillance has revolutionized the treatment of many cancers. Immune checkpoint inhibitor (ICI) monoclonal antibodies (mAb) reactivate cancer patients’ (pts’) immune systems to attack tumor cells thus eliciting response even in advanced disease. Unfortunately, durable response rates remain relatively low (~25%), and it is currently unclear what limits ICI response. Retrospective analyses of clinical pharmacology data reveal a strong correlation between elevated ICI clearance (CL) and reduced ICI response that is also associated with cancer cachexia, though independent of circulating ICI levels or ICI target receptor occupancy. Suppressive immune populations are elevated in pts with non-small cell lung cancer (NSCLC) and in multiple animal models of cachexia, but how these immune populations differ in numbers or function in cachectic vs. non-cachectic pts is poorly understood. The neonatal Fc receptor, FcRn (FCGRT), is a key mediator of IgG and albumin homeostasis with dual roles in recycling (i.e. slowing the CL of) both IgG and albumin in immune cells. Project Hypothesis: FcRn modulation in myeloid populations, triggered by yet unidentified cachexia-associated signaling, leads to elevated CL and poor ICI response. Preliminary data: 1) murine models replicate increased pembro CL in tumor-bearing cachectic mice relative to non-cachectic tumor-bearing mice and tumor-free controls; 2) increased CL of other mAbs, including anti-murine PD-1 mAb RMP1-14 in cachectic mice relative to non-cachectic mice; 3) decreased Fcgrt in liver of cachectic vs. non-cachectic mice; 4) immunosuppressive immune cell populations are elevated in pts with NSCLC and correlate with poor ICI responses; 5) increased myeloid and dendritic cell populations in pts and in mice with cancer-induced cachexia; and 6) paradoxical apparent elevation of FcRn protein in these immune cell populations in pts and mice. Project Objective: To identify mechanisms linking cachexia, elevated ICI mAb CL and poor response to ICI therapy. Specific Aims: Aim 1. To identify tissues with elevated mAb CL, altered FcRn and macrophages in cachectic mice. We expect to identify tissues/organs, immune cell populations, and FcRn expression/functional differences responsible for elevated CL in cachectic vs. non- cachectic mice. Aim 2. To determine whether cachexia affects myeloid-derived immune cells leading to poor ICI efficacy. We expect cachexia will alter myeloid-derived immune populations and FcRn function resulting in poor ICI mAb anti-tumor responses. Aim 3. To determine how cachexia affects anti-tumor immunity and pembro CL in NSCLC pts. We expect myeloid immune populations from cachectic pts will display modulated FcRn expression and function that drives decreased efficacy and elevated CL of anti-PD-1 treatment. Impact: Despite the remarkable promise of ICI therapies, durable responses remain rare, and causes of resistance unclear. Our project interrogates probable mechanisms linking poor clinical outcomes to ICI clearance and cachexia in NSCLC, which may reveal improved strategies for broadly overcoming ICI resistance.

概括癌细胞逃避免疫监视能力的治疗靶向彻底改变了治疗在许多癌症中。免疫检查点抑制剂（ICI）单克隆抗体（MAB）重新激活癌症患者的患者（PTS的）免疫系统攻击肿瘤细胞，因此即使在晚期疾病中也会引起反应。很遗憾，耐用的响应率仍然相对较低（约25％），目前尚不清楚什么限制ICI响应。临床药理学数据的回顾性分析揭示了ICI升高之间的密切相关性清除率（CL）和ICI响应降低，但也与癌症恶病质有关，尽管独立于循环ICI水平或ICI目标受体占用。 PTS中抑制性免疫量升高与非小细胞肺癌（NSCLC）和多种死亡的动物模型一起使用，但是这些如何免疫在cachecic和非核PT中，人群的数量或功能差异很差。新生儿 FC受体FCRN（FCGRT）是IgG和白蛋白稳态的关键介体，在回收中具有双重作用（即减慢免疫细胞中IgG和白蛋白的CL。项目假设：髓样的FCRN调节人群是由尚未确定的卡氏症相关信号引发的，导致CL和差的ICI升高回复。初步数据：1）鼠模型在肿瘤安全小鼠中复制pembro CL的增加相对于非伴有肿瘤的小鼠和无肿瘤对照； 2）增加其他mab的Cl，包括相对于非型小鼠，化学小鼠中的抗毛线PD-1 MAB RMP1-14； 3）改善了肝脏的FCGRT cachecic vs.非伴侣小鼠； 4）免疫抑制性免疫核管种群在PT中升高 NSCLC并与ICI反应不良相关； 5）增加了PTS和IN中的髓样细胞群体患有癌症诱发的恶病质的小鼠； 6）在这些免疫中FCRN蛋白的矛盾外观升高 PT和小鼠中的细胞群体。项目目标：识别与Cachexia联系起来的机制，ICI升高 MAB CL和对ICI治疗的反应不佳。具体目的：目标1。识别具有升高单元cl的组织化学小鼠的FCRN和巨噬细胞改变。我们期望识别组织/器官，免疫细胞种群以及CACHEC中CL升高的FCRN表达/功能差异。非目标2。确定恶病质是否影响髓样衍生的免疫细胞导致较差 ICI效率。我们预计恶病质会改变髓样衍生的免疫吞吐量和FCRN功能，从而导致 ICI mAb抗肿瘤反应差。目标3。确定恶病质如何影响抗肿瘤免疫组织化学和 NSCLC PT中的Pembro CL。我们预计化学PTS的髓样免疫量将显示调制 FCRN的表达和功能可促进效率降低和抗PD-1处理的CL升高。影响：尽管ICI疗法有很大的希望，但持久的反应仍然很少，并且是抗药性的原因不清楚。我们的项目询问有问题的机制，将不良临床结果与ICI清除和 NSCLC中的病原体，这可能揭示了改进的策略，以广泛克服ICI耐药性。