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：
10504585
负责人：
Christopher C. Coss
金额：
$ 63.99万
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/10504585
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 checkpoint inhibitor Immune system Immunoglobulin G Immunologic Surveillance Immunosuppression Laboratories Link Liver Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of pancreas Mediating Mediator of activation protein Methods Monoclonal Antibodies Mus Myelogenous Myeloid Cells Non-Small-Cell Lung Carcinoma Nonmetastatic Organ Outcome Patients Phenotype Play Population 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 cancer cachexia cancer cell checkpoint therapy cytokine improved in vivo evaluation macrophage 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.

概括针对癌细胞逃避免疫监视的能力的治疗靶点彻底改变了治疗方法免疫检查点抑制剂 (ICI) 单克隆抗体 (mAb) 可重新激活癌症患者的免疫功能。（pts）免疫系统攻击肿瘤细胞，从而即使在晚期疾病中也会引起反应，不幸的是，持久缓解率仍然相对较低（约 25%），目前尚不清楚是什么限制了 ICI 的缓解。临床药理学数据的回顾性分析揭示了 ICI 升高与清除率 (CL) 和 ICI 反应减少也与癌症恶病质有关，尽管与癌症恶病质无关患者中循环 ICI 水平或 ICI 靶受体占有率升高。与非小细胞肺癌（NSCLC）和多种恶病质动物模型中，但这些免疫如何恶病质与非恶病质患者的群体数量或功能差异尚不清楚。 Fc 受体 FcRn (FCGRT) 是 IgG 和白蛋白稳态的关键介质，在回收中具有双重作用（即减缓免疫细胞中 IgG 和白蛋白的 CL 项目假设：骨髓中的 FcRn 调节。由尚未确定的恶病质相关信号触发的人群会导致 CL 升高和 ICI 较差初步数据：1) 小鼠模型在荷瘤恶病质小鼠中复制了增加的 pembro CL。相对于非恶病质肿瘤小鼠和无肿瘤对照小鼠；2) 其他单克隆抗体的 CL 增加，包括相对于非恶病质小鼠，抗鼠 PD-1 mAb RMP1-14 的肝脏 Fcgrt 降低；恶病质小鼠与非恶病质小鼠相比；4) 患有恶病质小鼠的免疫抑制性免疫细胞群升高； NSCLC 并与较差的 ICI 反应相关；5) 患者和患者中骨髓细胞和树突状细胞数量增加；患有癌症引起的恶病质的小鼠；以及 6) 这些免疫中 FcRn 蛋白的反常明显升高患者和小鼠的细胞群项目目标：确定恶病质与 ICI 升高之间的联系机制。 mAb CL 和对 ICI 治疗反应不佳具体目标：目标 1. 识别 mAb CL 升高的组织，恶病质小鼠中 FcRn 和巨噬细胞的改变我们期望鉴定组织/器官、免疫细胞。人群和 FcRn 表达/功能差异导致恶病质与非恶病质中 CL 升高目标 2. 确定恶病质是否会影响骨髓源性免疫细胞，从而导致不良反应。我们预计恶病质会改变骨髓源性免疫群体和 FcRn 功能，从而导致 ICI 功效。 ICI mAb 抗肿瘤反应较差目标 3. 确定恶病质如何影响抗肿瘤免疫和 NSCLC 患者中的 pembro CL 我们预计来自恶病质患者的骨髓免疫群体将表现出调节。 FcRn 表达和功能导致抗 PD-1 治疗疗效下降和 CL 升高。尽管 ICI 疗法有着显着的前景，但持久的反应仍然很少见，而且耐药性的原因我们的项目探讨了不良临床结果与 ICI 清除之间的可能机制。 NSCLC 中的恶病质，这可能揭示了广泛克服 ICI 耐药性的改进策略。