Abstract
Programmed cell death ligand-1 (PD-L1) is typically produced by cancer cells and suppresses immunity through the receptor PD-1 expressed on T cells. However, the role of PD-L1 and PD-1 in regulating pain and neuronal function is unclear. Here we report that both melanoma and normal neural tissues including dorsal root ganglion (DRG) produce PD-L1 that can potently inhibit acute and chronic pain. Intraplantar injection of PD-L1 evoked analgesia in naive mice via PD-1, whereas PD-L1 neutralization or PD-1 blockade induced mechanical allodynia. Mice lacking Pd1 (Pdcd1) exhibited thermal and mechanical hypersensitivity. PD-1 activation in DRG nociceptive neurons by PD-L1 induced phosphorylation of the tyrosine phosphatase SHP-1, inhibited sodium channels and caused hyperpolarization through activation of TREK2 K+ channels. PD-L1 also potently suppressed nociceptive neuron excitability in human DRGs. Notably, blocking PD-L1 or PD-1 elicited spontaneous pain and allodynia in melanoma-bearing mice. Our findings identify a previously unrecognized role of PD-L1 as an endogenous pain inhibitor and a neuromodulator.
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Acknowledgements
This study is supported by NIH RO1 grants NS87988, DE17794 and DE22743 and National Science Fund of China (NSFC) 31420103903. Y.H.K. was supported by the National Research Foundation of Korea (NRF) 2013R1A6A3A04065858.
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Contributions
G.C. developed the project, performed behavioral and histochemical experiments and prepared the final figures. Y.H.K. conducted electrophysiology in mouse and human DRG neurons. H. Li and H. Luo performed spinal cord recordings and behavioral test in bonce caner model under the guidance of Y.-Q.Z. D.-L.L. performed recordings in whole-mount mouse DRGs. Z.-J.Z. contributed to histochemistry in Pd1 knockout mice. M.L. did some in situ hybridization experiment. W.C. conducted some electrophysiology in mouse DRG neurons. R.-R.J. and Y.-Q.Z. supervised the project. R.-R.J., G.C. and Y.-Q.Z. wrote the paper.
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Integrated supplementary information
Supplementary Figure 1 PD-L1 secretion in melanoma cells and Pdl1 miRNA expression in mouse DRG neurons
(a) ELISA analysis showing PD-L1 secretion in culture medium collected from B16F10 mouse melanoma cell line or control medium (without cells). 1~1.5 × 106 cells were included per well. *P<0.05, two-tailed student t-test, n=3 cultures. Data are mean ± s.e.m. (b,c) In situ hybridization (ISH) image showing Pdl1 mRNA expression in mouse DRG neurons. (b) Left and middle panels, low and high magnification images of ISH with anti-sense probe. Scales, 50 and 20 μm. Right, high magnification image of double ISH and Nissl staining in mouse DRG neurons. Scale, 20 μm. (c) ISH image of sense probe showing the absence of Pdl1 mRNA expression in mouse DRG neurons. Scale, 50 μm.
Supplementary Figure 2 Spontaneous pain and mechanical sensitivity in naive mice and nivolumab binding in mouse DRG neurons and sciatic nerve
(a) Soluble PD-1 (sPD-1, 5 μg, i.pl.) does not induce spontaneous pain. n.s., not significant; n=5 mice/group. (b) Prevention of PD-L1 (5 μg, i.pl.) induced analgesia (increase in paw withdrawal threshold) by pretreatment of RMP1-14 (mouse anti-PD-1 antibody, 5 μg, i.pl.) or Nivolumab (human anti-PD-1 antibody, 10 μg, i.pl.). Human IgG was included as a control. *P<0.05, vs. human IgG/PD-L1, repeated measures Two-Way ANOVA, n = 4 mice/group. Arrows indicate drug injections. Human IgG or monoclonal antibody was injected 30 min prior to the injection of PD-L1. BL, baseline. (c) Nivolumab (10 mg/ml) binds DRG neurons and sciatic nerve axons in WT but not Pd1 KO mice. Nivolumab is detected by the 2nd antibody (mouse monoclonal HP6025 Anti-Human IgG4, FITC; 1.25 mg/ml). Arrows indicate nerve fibers. Data are mean ± s.e.m.
Supplementary Figure 3 PD-L1 or anti-PD-1 treatment fails to change mechanical sensitivity in Pd1−/− mice
(a,b) von Frey test showing the effects of PD-L1 (5 μg, i.pl.) and RMP1-14 (mouse anti-PD-1 antibody, 5 μg, i.pl.) on paw withdrawal threshold in WT and KO mice. (a) PD-L1 increases withdrawal threshold in WT but not KO mice. (b) RMP1-14 decreases withdrawal threshold in WT but not KO mice. *P<0.05, #P<0.05, vs. baseline (BL), two-way repeated ANOVA, n = 6 mice/group. Data are mean ± s.e.m.
Supplementary Figure 4 Pd1−/− mice display normal central innervations in the spinal cord dorsal horn
(a) Immunostaining of IB4, CGRP and NF200 on L4-spinal cord sections from WT or Pd1−/− mice. Scale bar, 100 μm. Note the central innervations of primary afferents in the spinal cord are normal in KO mice. (b) Nissl staining on L4-spinal cord sections showing normal morphology of spinal cord dorsal horn of KO mice. Scale bar, 100 μm. (c) Quantification of immunofluorescence of IB4, CGRP, and NF200 staining in the dorsal horn of WT and KO mice. n.s., not significant., Two-tailed Student’s t-test, n = 4 mice/group. Three to five sections from each animal were included for quantification. Data are mean ± s.e.m.
Supplementary Figure 5 Pd1−/− mice display normal distribution patterns of C-fiber and A-fiber neurons and have no neuronal loss in DRGs
(a) Immunostaining of IB4, CGRP and NF200 and Nissl staining on L4-DRG sections from WT or Pd1−/− mice. Scale bar, 100 μm. Note that KO mice have normal distribution patterns of different sensory populations of DRG neurons. (b, c) Quantification of the percentages of IB4-binding, CGRP-IR, and NF200-IR neurons (b) and the total numbers of neurons with Nissl staining (c) in DRG sections from WT and Pd1−/− mice. All the DRG sections (14 μm) were collected and every 5th section was used for respective immunostaining or Nissl staining. n = 4 mice/group. n.s., not significant; two-tailed Student’s t-test. Data are mean ± s.e.m.
Supplementary Figure 6 Spinal application of PD-L1 suppresses excitatory synaptic transmission in lamina IIo neurons in spinal cord slices and inhibits neuropathic pain and baseline pain in mice
(a-d) Patch clamp recordings of excitatory synaptic transmission and quantification of frequency and amplitude of spontaneous excitatory postsynaptic synaptic currents (sEPSCs) in lamina IIo neurons of spinal cord slices of naïve mice. (a) Perfusion with PD-L1 (30 ng/ml) reduces the frequency and amplitude of sEPSCs. Left, traces of sEPSCs before (1) and after (2) PD-L1 perfusion. Right, frequency (upper) and amplitude (bottom) of sEPSCs. *P < 0.05, before vs. after the treatment, paired two-tailed Student’s t-test, n =14 neurons/3-4 mice. (b) Perfusion with sPD-1 (30 ng/ml) increases the frequency (upper) not the amplitude (bottom) of sEPSCs. *P < 0.05, compared with control, n.s., no significance, paired two-tailed Student’s t-test, n = 9 neurons/3 mice. (c) Incubation of spinal cord slices with Nivolumab (300 ng/ml, 3 h) increases the frequency of sEPSCs. *P < 0.05, one-way ANOVA, followed by Bonferroni’s post-hoc test, n = 21 neurons/3-4 mice. (d) Incubation with Nivolumab (300 ng/ml, 3 h) blocks the effects of PD-L1. n.s., no significance, n = 6 neurons/3 mice. The data are mean ± s.e.m.
Supplementary Figure 7 Spinal application of PD-L1 inhibits mechanical hypersensitivity and firing of spinal WDR neurons in a model of bone cancer in rats.
(a) Inhibition of bone cancer-induced mechanical allodynia by i.t. PD-L1 in rats. *P < 0.05, vs. baseline (BL), §P < 0.05, vs. pre-injection baseline on post-tumor implantation day 14 (PTD 14), #P < 0.05, vs. vehicle, repeated measures two-Way ANOVA, n = 5 rats/group. Arrow indicates drug injection. (b,c) Suppression of brush, von Frey filaments, and pinch evoked spikes of spinal WDR neurons by PD-L1 (20 μg, i.t., 3 h) on post-tumor implantation day 14. (b) Histograms of evoked spikes of WDR neuron firing by brush, von Frey filaments, and pinch stimulation. (c) Mean spikes of WDR neurons following low and high intensity mechanical stimuli. *P < 0.05, vs. vehicle control, paired student’s t-test, n = 5 rats/group. (d,e) Enhancement of brush, von Frey filaments, and pinch evoked spikes of WDR neurons by intrathecal Nivolumab (10 μg, 1 h) on post-tumor implantation day 8. (d) Histograms of evoked spikes of WDR neurons firing by brush, von Frey filaments, and pinch stimulation. (e) Mean spikes of WDR neurons following low and high intensity mechanical stimuli. *P < 0.05, vs. vehicle; #P < 0.05 vs. human IgG, one-Way ANOVA, n = 4-5 rats/group. Data are mean ± s.e.m.
Supplementary Figure 8 PD-L1 induces phosphorylation of SHP1 in mouse DRG neurons
(a) Double IHC and ISH staining shows co-localization of pSHP-1 and Pd1 mRNA in DRG neurons 30 min after intrathecal PD-L1 injection (1 μg). Scale, 50 μm. (b) Enlarged images of the boxes in a. Arrows indicate the double-labeled neurons. Scale, 20 μm. (c) PD-L1 treatment (10 ng/ml, 30 min) increases phosphorylation of SHP-1 (pSHP-1) in dissociated mouse DRG neurons. Left, pSHP-1 immunostaining and the effects of PD-L1 and the SHP-1 inhibitor SSG (11 μM). Scales, 50 μm. Right, intensity of immunofluorescence of pSHP-1-positive neurons. *P < 0.05, n = 98-104 neurons from 3 separate dishes, one-Way ANOVA, n.s., no significance. Data are mean ± s.e.m.
Supplementary Figure 9 TREK2 activation by PD-L1 in CHO cells and schematic illustration of PD-L1-induced silencing of nociceptive neurons
(a) TREK2 immunostaining in mouse DRG. Scale, 50 μm. (b) PD-L1 increases TREK2-mediated outward currents (up-left and up-right), causes a negative shift in the reversal potential (Erev) of the outward currents (low-left), and changes RMP (low-right) via PD-1. CHO cells were co-transfected with KCNK10 cDNA (encoding TREK2) and PDCD1 cDNA (encoding PD-1) or transfected with KCNK10 or PDCD1 cDNA alone. Note that PD-L1 fails to cause these changes when CHO cells only express TREK2 or PD-1. *P < 0.05, One-Way ANOVA, n = 6-8 cells/2 cultures. Also see Figure 6d,e. Data are mean ± s.e.m. (c) Schematic illustration of the mechanisms by which PD-L1 silences nociceptive neurons, via suppression of action potentials through voltage-gated sodium channels (VGSCs) or/and via hyperpolarization through TREK2 potassium channels.
Supplementary Figure 10 PD-1 immunofluorescence in DRG neurons and nerve axons of human tissue sections
(a,b) PD-1 immunofluorescence in human DRG neurons and dorsal root axons. Right panels in (a) and (b) showing the absence of PD-1 immunostaining by the blocking peptide. Blue DAPI staining shows all cell nuclei in DRG and nerve sections. Scales, 50 μm. (c) Double immunostaining of PD-1 and NF200 in human spinal nerve axons. The Box in the left panel is enlarged in three panels. Scales, 50 μm. Arrows indicate the double-labeled axon.
Supplementary Figure 11 Intraplantar (i.pl.) injection of soluble PD-1 (sPD-1) evokes spontaneous pain and mechanical allodynia in melanoma mice
(a,b) Induction of spontaneous pain (a, flinching/licking behavior) and evoked pain (b, mechanical allodynia) by soluble PD-1 (sPD-1) following i.pl. injection at MCI-4w. Note a rapid onset of spontaneous pain by sPD-1 within 30 min. Arrow indicates drug injection. *P<0.05, compared with vehicle, repeated measures two-way ANOVA (b). n = 6 and 7 mice per group.
Supplementary Figure 12 Intraplantar (i.pl.) injection of soluble PD-1 (sPD1) does not change immune responses in melanoma-bearing hindpaw skin in the acute phase
(a) sPD1 (5 μg, i.pl.), given to melanoma mice at 4w does not change immune responses in hindpaw skins at 3 h after the injection. Note that relative mRNA levels (shown by quantitative RT-PCR and normalized with GAPDH) of TNF, IL-1B, Il-6, IFNG, CCL2, CD2, CD8, and CD68 all increase in tumor bearing skins. *P<0.05, vs. contralateral control (for all 8 markers), n.s., no significance (for all 8 markers), one-Way ANOVA, n = 5 mice/group. All the data are expressed as mean ± s.e.m. (b) Primer sequences used for qPCR in the experiment.
Supplementary Figure 13 Pd1-targeting siRNA decreases PD-1 expression in DRG and sciatic nerve but not spinal cord dorsal horn tissues
(a) Western blot analysis showing the effects of Pd1-targeting siRNA and non-targeting (NT) control siRNA on PD-1 expression in DRG, sciatic nerve, and spinal cord tissues. Low panels, quantification of PD-1 expression in different mouse tissues. *P < 0.05, PD-1 vs. NT, n.s., no significance, two-tailed student’s t-test, n = 5 mice/group. siRNA was applied via peri sciatic injection (2 μg) given at MCI-4w. (b) Uncut gels for PD-1 and GAPDH western blots of DRG, sciatic nerve, and dorsal horn tissues. The represented blots are highlighted in the red boxes, respectively. The images (flipped) show non-targeting (NT) siRNA treatment on the left and PD-1 siRNA treatment on the right.
Supplementary Figure 14 Induction of mechanical allodynia and spontaneous pain by systemic or local injection of anti-PD-1 antibodies and SHP-1 inhibitor in melanoma mice
(a,b) Intravenous RMP1-14 (mouse anti-PD-1 antibody, 10 mg/kg) induces mechanical allodynia (a) and spontaneous pain (b) in melanoma-bearing mice at MCI-4w. *P < 0.05, compared to control rat IgG2A, two-way ANOVA, repeated measures (a), or student’s t-test (b), n = 6 mice/group. Drug injection is indicated by arrow. (c) Intrathecal injection of Nivolumab (1 and 10 μg, n = 6 and 7 mice/group), given at MCI-4w (shown with the arrow), induces mechanical allodynia. *P < 0.05, compared with control human IgG4, repeated measures two-way ANOVA. (d) Intraplantar injection of Nivolumab (10 μg, n = 4 and 5 mice/group), given at MCI-4w (shown with the arrow), induces mechanical allodynia. *P < 0.05, compared with control human IgG4, repeated measures two-way ANOVA. (e) Induction of spontaneous pain (flinching/licking behavior) by SHP-1 inhibitor SSG (5 μg, i.pl.) given at MCI-4w. *P < 0.05, two-tailed student’s t-test. n = 5 mice/group. (f) Schematic illustration of PD-L1 evoked pain masking in melanoma. The pharmacological agents used in this study for targeting the PD-L1/PD-1 pathway are highlighted in purple. Data are mean ± s.e.m.
Supplementary Figure 15 Numbers of animals (mice and rats) used in this study
A total of 528 mice and 51 rats were used in this study. We also collected human DRGs from 9 donors.
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Supplementary Figures 1–15 (PDF 2961 kb)
Spontaneous pain in top left mouse
Video 1 (40 s) shows spontaneous pain in top left mouse. The bottom two control mice received vehicle injection and did not show spontaneous pain, despite massive growth of melanoma in a hindpaw. (AVI 19097 kb)
Spontaneous pain in top right mouse
Video 2 (40 s) shows spontaneous pain in top right mouse. The bottom two control mice received vehicle injection and did not show spontaneous pain, despite massive growth of melanoma in a hindpaw. (AVI 18443 kb)
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Chen, G., Kim, Y., Li, H. et al. PD-L1 inhibits acute and chronic pain by suppressing nociceptive neuron activity via PD-1. Nat Neurosci 20, 917–926 (2017). https://doi.org/10.1038/nn.4571
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DOI: https://doi.org/10.1038/nn.4571
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