Targeting checkpoint inhibitors for pain control

摘要 新兴的免疫疗法已显示出对各种癌症患者的疗效。靶向免疫 检查点蛋白，如程序性细胞死亡蛋白-1配体1（PD-L1）及其受体PD-1， 单克隆抗体挽救了癌症患者的生命。PD-L1被认为通过结合 T细胞上的PD-1受体免疫疗法也通过增加自身免疫产生副作用。我们最近 报道PD-1也由神经元表达（例如，背根神经节初级感觉神经元和脊髓 脊髓神经元）和巨噬细胞/破骨细胞，但PD-1在这些细胞类型中的功能仍有待验证 使用Pd 1条件性敲除（cKO）小鼠的特定品系。本研究的目的是探讨PD- L1/PD-1检查点通路通过神经元调控生理和病理性疼痛及阿片类镇痛， 免疫和神经胶质机制。为了确定PD-1的作用的细胞机制，我们将使用条件反射法。 敲除小鼠（cKO），在感觉神经元、小胶质细胞和巨噬细胞中选择性缺失Pd 1，以测试 根据假设和具体目标。目的1：检验PD-L1/PD-1级联控制的假设 目的2：检验PD-L1/PD-1级联反应在非损伤小鼠中的生理性疼痛和阿片类镇痛作用; 通过神经元、免疫和小胶质细胞调节炎性、术后、神经性和骨癌疼痛 目的3：确定PD-L1和纳武单抗对NHP中神经炎症或/和疼痛的作用 和人背根神经节。该项目的成功完成将验证PD-L1/PD-1轴在以下方面的重要作用： 疼痛控制这项研究还将为检查点通路激活剂的不同作用提供新的见解， 用于管理不同类型疼痛的抑制剂（炎性/术后/神经性疼痛vs. 癌症疼痛）。

Abstract Emerging immunotherapy has shown efficacy for patients with various cancers. Targeting the immune checkpoint proteins, such as programmed cell death protein-1 ligand 1 (PD-L1) and its receptor PD-1 using monoclonal antibodies has saved lives of cancer patients. PD-L1 was thought to suppress immunity via binding to PD-1 receptor on T cells. Immunotherapies also produce side effects by increasing autoimmunity. We recently reported that PD-1 is also expressed by neurons (e.g., dorsal root ganglia primary sensory neurons and spinal cord neurons) and macrophages/osteoclasts, but the function of PD-1 in these cell types remains to be validated using specific lines of Pd1 conditional knockout (cKO) mice. The goal of this study is to investigate how the PD- L1/PD-1 checkpoint pathway controls physiological and pathological pain and opioid analgesia via neuronal, immune, and glial mechanisms. To determine the cellular mechanisms of PD-1’s actions, we will use conditional knockout mice (cKO), with selective deletion of Pd1 in sensory neurons, microglia, and macrophages, to test the following hypotheses and specific aims. Aim 1: Test the hypothesis that PD-L1/PD-1 cascade controls physiological pain and opioid analgesia in non-injured mice; Aim 2: Test the hypothesis that PD-L1/PD-1 cascade regulates inflammatory, postoperative, neuropathic, and bone cancer pain via neuronal, immune, and microglial signaling in mice; Aim 3: Validate the actions of PD-L1 and nivolumab on neuroinflammation or/and pain in NHPs and in human DRG. Successful completion of this project will validate an important role of PD-L1/PD-1 axis in pain control. This study will also provide novel insights into distinct actions of checkpoint pathway activators and inhibitors for the management of different types of pain (inflammatory/postoperative/neuropathic pain vs. bone cancer pain).