Targeting checkpoint inhibitors for pain control

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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).