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

总结 针对癌细胞逃避免疫监视的能力的治疗已经彻底改变了治疗方法 许多癌症。免疫检查点抑制剂（ICI）单克隆抗体（mAb）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引起反应。不幸的是， 持续缓解率仍然相对较低（~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显示，ICI升高与 清除率（CL）和ICI反应降低，也与癌症恶病质相关，尽管独立于 循环ICI水平或ICI靶受体占有率。抑制性免疫群体在患者中升高 非小细胞肺癌（NSCLC）和多种恶病质动物模型，但这些免疫 恶病质患者与非恶病质患者的数量或功能不同的人群知之甚少。新生儿 Fc受体FcRn（FCGRT）是IgG和白蛋白稳态的关键介质，在再循环中具有双重作用（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 由尚未鉴定的恶病质相关信号触发的人群，导致CL升高和ICI不良 反应初步数据：1）小鼠模型在荷瘤恶病质小鼠中复制了pembro CL增加 相对于非恶病质荷瘤小鼠和无肿瘤对照; 2）其他mAb的CL增加，包括 与非恶病质小鼠相比，恶病质小鼠中的抗鼠PD-1 mAb RMP 1 - 14; 3） 恶病质与非恶病质小鼠; 4）免疫抑制性免疫细胞群在患有 与ICI反应差相关; 5）患者和非小细胞肺癌患者中髓样细胞和树突状细胞群增加， 癌症诱导的恶病质小鼠;和6）这些免疫细胞中FcRn蛋白的反常明显升高 患者和小鼠中的细胞群。项目目标：确定恶病质、ICI升高 mAb CL和对ICI治疗的不良反应。具体目标：目标1。为了鉴定mAb CL升高的组织， 改变恶病质小鼠的FcRn和巨噬细胞。我们希望能够识别组织/器官，免疫细胞， 人群，以及恶病质与非恶病质患者CL升高的FcRn表达/功能差异。 恶病质小鼠目标2.为了确定恶病质是否影响骨髓源性免疫细胞， ICI疗效。我们预计恶病质将改变骨髓源性免疫群体和FcRn功能，导致 ICI mAb抗肿瘤反应差。目标3。为了确定恶病质如何影响抗肿瘤免疫， NSCLC患者中的pembro CL。我们预期恶病质患者的髓系免疫群将显示出调节的 FcRn表达和功能导致抗PD-1治疗的疗效降低和CL升高。影响： 尽管ICI疗法有着显著的前景，但持久的反应仍然很少，耐药的原因是 不清楚我们的项目探讨了将不良临床结局与ICI清除联系起来的可能机制， 这可能揭示了广泛克服ICI耐药的改进策略。

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.