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).

Narrative Targeting the immune checkpoint inhibitory proteins, such as programmed cell death protein-1 ligand 1 (PD-L1) and its receptor PD-1 has saved many lives of cancer patients. The overall goal of this application is to investigate and validate how the PD-L1/PD-1 immune checkpoint cascade controls physiological and pathological pain and opioid analgesia via neuronal, immune, and glial regulations. Successful completion of this project will provide novel insights into distinct actions of checkpoint pathway activators and inhibitors for the management of different types of pain.