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

摘要 针对癌细胞逃避免疫监视的治疗靶点使治疗方法发生了革命性的变化。 在许多癌症中。免疫检查点抑制物(ICI)单抗(MAb)重新激活癌症患者的 (PTS‘)免疫系统攻击肿瘤细胞，从而即使在晚期疾病也能引起反应。不幸的是， 持久应答率仍然相对较低(约25%)，目前尚不清楚是什么限制了ICI的反应。 对临床药理学数据的回顾分析显示，ICI升高与 清除(CL)和降低的ICI反应也与癌症恶病质有关，尽管独立于 循环ICI水平或ICI靶受体占有率。PTS患者的抑制性免疫群体升高 与非小细胞肺癌(NSCLC)和在多种动物模型中的恶病质，但这些免疫 恶病质与非恶病质PTS的人群在数量或功能上存在差异，目前对此知之甚少。新生儿 Fc受体FcRN(FCGRT)是一种重要的免疫球蛋白和白蛋白稳态的调节因子，在循环中具有双重作用。 减缓免疫细胞中免疫球蛋白和白蛋白的化学发光。项目假说：FcRN在髓系中的调制 由尚未确定的恶病质相关信号触发的人群导致CL升高和ICI较差 回应。初步数据：1)小鼠模型在荷瘤恶病质小鼠体内复制增厚的膜CL 相对于非恶病质荷瘤小鼠和无肿瘤对照：2)其他单抗的CL增加，包括 抗小鼠PD-1单抗RMP1-14在恶病质小鼠与非恶病质小鼠的比较；3)降低了小鼠肝脏的Fcgrt 恶病质小鼠与非恶病质小鼠比较；4)免疫抑制免疫细胞群在慢性粒细胞白血病患者中升高 NSCLC与ICI反应差有关；5)PTS和INS中髓系细胞和树突状细胞数量增加 癌症诱发恶病质的小鼠；以及6)这些免疫中FcRN蛋白的反常明显升高 PTS和小鼠的细胞群。项目目标：确定恶病质、ICI升高 单抗CL和ICI治疗反应差。具体目的：目的1.鉴定mAbCL升高的组织， 恶病质小鼠FcRN和巨噬细胞的改变。我们希望识别组织/器官，免疫细胞 恶病质和非恶病质中CL升高的人群和FcRN表达/功能差异 恶病质老鼠。目的2.确定恶病质是否会影响髓系免疫细胞，从而导致 ICI疗效。我们预计恶病质会改变髓系来源的免疫群体和FcRN功能，导致 ICI单抗抗肿瘤反应差。目的3.确定恶病质如何影响抗肿瘤免疫和 非小细胞肺癌患者中的Pbro CL。我们预计来自恶病质患者的髓系免疫群体将表现出调节 FcRN的表达和功能驱动抗PD-1治疗的疗效降低和CL增加。影响： 尽管ICI疗法前景看好，但持久的反应仍然很少见，而且耐药的原因 不清楚。我们的项目询问了将不良临床结果与ICI清除和 NSCLC中的恶病质，这可能揭示出广泛克服ICI耐药性的改进策略。

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.