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Volume 23, Issue 5
  • ISSN: 1570-159X
  • E-ISSN: 1875-6190

Abstract

Background

Oral cancer causes intense pain at the primary site, and such pain can impair oral functions. However, the underlying mechanisms for oral cancer pain are still not fully understood. In the present study, it is investigated whether programmed cell death protein 1 (PD-1) is involved in the development of oral cancer pain.

Methods

RMP1-14, a specific anti-PD-1 antibody, was injected into spinal trigeminal nucleus caudalis (Sp5C) and measured pain behaviors using von Frey filaments and dolognawmeter. Western blotting and immunofluorescence staining were performed to analyze the expression of PD-1 and tumor necrosis factor alpha (TNFα) in the Sp5C.

Results

It was observed that the PD-1 antibody significantly inhibited mechanical hypersensitivity and functional allodynia in our oral cancer pain mouse model. Moreover, we found that TNFα was highly upregulated in the Sp5C following the induction of oral cancer pain and that intra-Sp5C injection of the PD-1 antibody diminished the upregulation of TNFα. It was found that genetic deletion of TNFα or its receptor antagonism synergized the analgesic effect of PD-1 antibody on oral cancer pain.

Conclusion

Our results suggest that PD-1 in the Sp5C contributes to oral cancer pain by altering TNFα signaling in the trigeminal nociceptive system, and PD-1 could be targeted to develop a novel approach for oral cancer pain management.

© 2025 Bentham Science Publishers
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2024-12-09
2025-03-27

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References

  1. MazeronR. TaoY. LusinchiA. BourhisJ. Current concepts of management in radiotherapy for head and neck squamous-cell cancer.Oral Oncol.2009454-540240810.1016/j.oraloncology.2009.01.01019375379
     [Google Scholar]
  2. ShahJ.P. GilZ. Current concepts in management of oral cancer: Surgery.Oral Oncol.2009454-539440110.1016/j.oraloncology.2008.05.01718674952
     [Google Scholar]
  3. YangY. ZhangP. LiW. Comparison of orofacial pain of patients with different stages of precancer and oral cancer.Sci. Rep.20177120310.1038/s41598‑017‑00370‑x28303010
     [Google Scholar]
  4. SchmidtB.L. What pain tells us about cancer.Pain2015156Suppl 1)(Suppl. 1S32S3410.1097/j.pain.000000000000009925789434
     [Google Scholar]
  5. DiosP.D. LestónJ.S. Oral cancer pain.Oral Oncol.201046644845110.1016/j.oraloncology.2010.02.01720308009
     [Google Scholar]
  6. JiR.R. ChamessianA. ZhangY.Q. Pain regulation by non-neuronal cells and inflammation.Science2016354631257257710.1126/science.aaf892427811267
     [Google Scholar]
  7. JungerH. SorkinL.S. Nociceptive and inflammatory effects of subcutaneous TNF α.Pain200085114515110.1016/S0304‑3959(99)00262‑610692613
     [Google Scholar]
  8. SchachteleS.J. HuS. ShengW.S. MutnalM.B. LokensgardJ.R. Glial cells suppress postencephalitic CD8+ T lymphocytes through PD‐L1.Glia201462101582159410.1002/glia.2270124890099
     [Google Scholar]
  9. TanZ.J. JuS.H. HuangX. GuY.K. SuZ.D. Glial cells function as neural stem cells and progenitor cells.Sheng Li Xue Bao201769220721728435980
     [Google Scholar]
  10. LamD.K. SchmidtB.L. Orofacial pain onset predicts transition to head and neck cancer.Pain201115251206120910.1016/j.pain.2011.02.00921388740
     [Google Scholar]
  11. ScheffN.N. YeY. BhattacharyaA. MacRaeJ. HickmanD.N. SharmaA.K. DolanJ.C. SchmidtB.L. Tumor necrosis factor alpha secreted from oral squamous cell carcinoma contributes to cancer pain and associated inflammation.Pain2017158122396240910.1097/j.pain.000000000000104428885456
     [Google Scholar]
  12. ButteM.J. KeirM.E. PhamduyT.B. SharpeA.H. FreemanG.J. Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses.Immunity200727111112210.1016/j.immuni.2007.05.01617629517
     [Google Scholar]
  13. SharmaP. AllisonJ.P. The future of immune checkpoint therapy.Science20153486230566110.1126/science.aaa817225838373
     [Google Scholar]
  14. ChenG. KimY.H. LiH. LuoH. LiuD.L. ZhangZ.J. LayM. ChangW. ZhangY.Q. JiR.R. PD-L1 inhibits acute and chronic pain by suppressing nociceptive neuron activity via PD-1.Nat. Neurosci.201720791792610.1038/nn.457128530662
     [Google Scholar]
  15. YaoA. LiuF. ChenK. TangL. LiuL. ZhangK. YuC. BianG. GuoH. ZhengJ. ChengP. JuG. WangJ. Programmed death 1 deficiency induces the polarization of macrophages/microglia to the M1 phenotype after spinal cord injury in mice.Neurotherapeutics201411363665010.1007/s13311‑013‑0254‑x24853068
     [Google Scholar]
  16. BertrandF. MontfortA. MarcheteauE. ImbertC. GilhodesJ. FilleronT. RochaixP. Andrieu-AbadieN. LevadeT. MeyerN. ColaciosC. SéguiB. TNFα blockade overcomes resistance to anti-PD-1 in experimental melanoma.Nat. Commun.201781225610.1038/s41467‑017‑02358‑729273790
     [Google Scholar]
  17. BertrandF. RochotteJ. ColaciosC. MontfortA. Andrieu-AbadieN. LevadeT. BenoistH. SéguiB. Targeting TNF alpha as a novel strategy to enhance CD8+T cell-dependent immune response in melanoma?OncoImmunology201651e106849510.1080/2162402X.2015.106849526942089
     [Google Scholar]
  18. LamD.K. DangD. ZhangJ. DolanJ.C. SchmidtB.L. Novel animal models of acute and chronic cancer pain: A pivotal role for PAR2.J. Neurosci.20123241141781418310.1523/JNEUROSCI.2399‑12.201223055487
     [Google Scholar]
  19. Romero-ReyesM. AkermanS. NguyenE. VijjeswarapuA. HomB. DongH.W. CharlesA.C. Spontaneous behavioral responses in the orofacial region: A model of trigeminal pain in mouse.Headache201353113715110.1111/j.1526‑4610.2012.02226.x22830495
     [Google Scholar]
  20. BaiQ. LiuS. ShuH. TangY. GeorgeS. DongT. SchmidtB.L. TaoF. TNFα in the trigeminal nociceptive system is critical for temporomandibular joint pain.Mol. Neurobiol.201956127829110.1007/s12035‑018‑1076‑y29696511
     [Google Scholar]
  21. CrawfordJ. LiuS. TaoR. KramerP. BenderS. TaoF. Ketogenic diet mitigates opioid-induced hyperalgesia by restoring short-chain fatty acids-producing bacteria in the gut.Pain20241659e106e11410.1097/j.pain.000000000000321238452211
     [Google Scholar]
  22. LiuS. ShuH. CrawfordJ. MaY. LiC. TaoF. Optogenetic activation of dopamine receptor D1 and D2 neurons in anterior cingulate cortex differentially modulates trigeminal neuropathic pain.Mol. Neurobiol.202057104060406810.1007/s12035‑020‑02020‑232654077
     [Google Scholar]
  23. LiuS. TangY. ShuH. TatumD. BaiQ. CrawfordJ. XingY. LoboM.K. BellingerL. KramerP. TaoF. Dopamine receptor D2, but not D1, mediates descending dopaminergic pathway-produced analgesic effect in a trigeminal neuropathic pain mouse model.Pain2019160233434410.1097/j.pain.000000000000141430325872
     [Google Scholar]
  24. MaY. LiuS. ShuH. CrawfordJ. XingY. TaoF. Resveratrol alleviates temporomandibular joint inflammatory pain by recovering disturbed gut microbiota.Brain Behav. Immun.20208745546410.1016/j.bbi.2020.01.01632001342
     [Google Scholar]
  25. ShuH. LiuS. CrawfordJ. TaoF. A female-specific role for trigeminal dynorphin in orofacial pain comorbidity.Pain2023164122801281110.1097/j.pain.000000000000298037463238
     [Google Scholar]
  26. ShuH. LiuS. TangY. SchmidtB.L. DolanJ.C. BellingerL.L. KramerP.R. BenderS.D. TaoF. A pre-existing myogenic temporomandibular disorder increases trigeminal calcitonin gene-related peptide and enhances nitroglycerin-induced hypersensitivity in mice.Int. J. Mol. Sci.20202111404910.3390/ijms2111404932516986
     [Google Scholar]
  27. TangY. LiuS. ShuH. XingY. TaoF. AMPA receptor GluA1 Ser831 phosphorylation is critical for nitroglycerin-induced migraine-like pain.Neuropharmacology201813346246910.1016/j.neuropharm.2018.02.02629486167
     [Google Scholar]
  28. TangY. LiuS. ShuH. YanagisawaL. TaoF. Gut microbiota dysbiosis enhances migraine-like pain via TNFα upregulation.Mol. Neurobiol.202057146146810.1007/s12035‑019‑01721‑731378003
     [Google Scholar]
  29. DolanJ.C. LamD.K. AchdjianS.H. SchmidtB.L. The dolognawmeter: A novel instrument and assay to quantify nociception in rodent models of orofacial pain.J. Neurosci. Methods2010187220721510.1016/j.jneumeth.2010.01.01220096303
     [Google Scholar]
  30. CalvoM. DawesJ.M. BennettD.L.H. The role of the immune system in the generation of neuropathic pain.Lancet Neurol.201211762964210.1016/S1474‑4422(12)70134‑522710756
     [Google Scholar]
  31. KwiatkowskiK. MikaJ. The importance of chemokines in neuropathic pain development and opioid analgesic potency.Pharmacol. Rep.201870482183010.1016/j.pharep.2018.01.00630122168
     [Google Scholar]
  32. Cervera-CarrasconV. SiuralaM. SantosJ.M. HavunenR. TähtinenS. KarellP. SorsaS. KanervaA. HemminkiA. TNFa and IL-2 armed adenoviruses enable complete responses by anti-PD-1 checkpoint blockade.OncoImmunology201875e141290210.1080/2162402X.2017.141290229721366
     [Google Scholar]
  33. BashamJ.H. GeigerT.L. Opposing effects of PD-1/PD-L1/L2 engagement and IFN-γ/TNF-α in the treatment of AMLw/Anti-CD33 chimeric antigen receptor modified T cells.Blood2016128225891589110.1182/blood.V128.22.5891.5891
     [Google Scholar]
  34. KottkeT. EvginL. ShimK.G. RommelfangerD. BoisgeraultN. ZaidiS. DiazR.M. ThompsonJ. IlettE. CoffeyM. SelbyP. PandhaH. HarringtonK. MelcherA. VileR. Subversion of NK-cell and TNFα immune surveillance drives tumor recurrence.Cancer Immunol. Res.20175111029104510.1158/2326‑6066.CIR‑17‑017529038298
     [Google Scholar]
  35. WangX. YangL. HuangF. ZhangQ. LiuS. MaL. YouZ. Inflammatory cytokines IL-17 and TNF-α up-regulate PD-L1 expression in human prostate and colon cancer cells.Immunol. Lett.201718471410.1016/j.imlet.2017.02.00628223102
     [Google Scholar]
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Programmed Cell Death Protein 1 Contributes to Oral Cancer Pain via Regulating Tumor Necrosis Factor Alpha in the Spinal Trigeminal Nucleus Caudalis
Curr. Neuropharmacol. 23, 594 (2025); https://doi.org/10.2174/1570159X23666241209160039
/content/journals/cn/10.2174/1570159X23666241209160039
/content/journals/cn/10.2174/1570159X23666241209160039
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  • Article Type:     Research Article
Keyword(s): functional allodynia; hypersensitivity; Oral cancer pain; programmed cell death protein 1; spinal trigeminal nucleus caudalis; tumor necrosis factor-alpha

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