PD-1 axis and pain modulation
| Mechanism | Finding | Effect | Reference |
|---|---|---|---|
| Neuroinflammation | Leukocyte infiltration, glial cell activation, and production of inflammatory mediators | Pain mechanisms in DRG, sciatic nerve, and SDH | [38–47] |
| PD-L1 upregulation on microglial cells, astrocytes, and mononuclear cells near meninges in high inflammation areas | Glial cells involvement | [48] | |
| PD-1/PD-L1 suppresses the expression of pro-inflammatory cytokines and induces M2 polarization. | Microglia activation | [49] | |
| Tumor-induced inflammation via cytokines and growth factors sensitizes nociceptive neurons. | Increasing hypersensitivity and excitability of nociceptive neurons | [50] | |
| Cancer cells create an acidic microenvironment that activates ASICs on nociceptive neurons. | Pain chronification | [51] | |
| Upregulation of sodium channels, sensory neuron sprouting, and pain signal amplification | Pain chronification | [36, 52] | |
| PD-1 agonists, (e.g., H-20) can modulate neuronal excitability and alleviate both acute and chronic pain. | PD-1 can be a target for designing analgesic peptides, but it may also potentially suppress anti-tumor immunity. | [53] | |
| PD-L1 expression in macrophages in the DRG and TLR4 activation | Potential effects on CIPN | [56] | |
| Neuromodulation | Nivolumab reduces GABA-induced currents in CNS neurons. | Impact of the PD-1 axis on pain mechanisms | [16, 36] |
| Effects on opioid mechanisms | PD-1 and MOR co-localization in DRG neurons, spinal nerve axons, and spinal cord axonal terminals | Anti-PD-1 treatment can affect opioid effects. | [60] |
| Chronic morphine administration elevates circulating CD8+ T-cells expressing PD-1. | Opioid-induced PD-1 expression | [61] | |
| Higher opioid use is associated with shorter PF and OS, and lower CD8+ T-cells in the tumor microenvironment. | Potential drug-drug interaction | [66–68] | |
| Effects on bone metastases | Nivolumab and Pdcd1-deficient mice experience less pain and destruction in bone cancer. | PD-1/PD-L1 pathway involvement in bone metastases and osteoclasts | [71] |
| PD-L1 promotes osteoclastogenesis through JNK activation and CCL2 secretion. | Nivolumab can block osteoclast formation. | [71] |
PD-1: programmed cell death-1; PD-L1: programmed cell death ligand-1; DRG: dorsal root ganglia; SDH: spinal cord dorsal horn; ASICs: acid-sensing ion channels; TLR4: Toll-like receptor 4; CIPN: chemotherapy-induced peripheral neuropathy; CNS: central nervous system; MOR: mu-opioid receptor; PF: progression-free; OS: overall survival; JNK: c-Jun N-terminal kinase; CCL2: chemokine C-C motif ligand 2