Role of Programmed Death Protein 1(PD-1) Signaling in Regulation of Oral Cancer Pain

Abstract

Pain as an initial symptom in oral cancer is difficult to manage. 70−80% of oral cancer cells secrete programmed death ligand 1 (PD-L1) to inhibit T cell function. PD-L1 and its receptor programmed cell death protein 1 (PD-1) is a critical checkpoint in immunoregulatory pathways. Their antibodies have been proven to be novel anti-cancer drugs to treat cancers. However, the role of PD-1 signaling in the regulation of oral cancer pain is unclear. In the present project, we used acute and chronic oral cancer pain mouse models. RMP1-14, a specific anti-PD-1 antibody, was injected into spinal trigeminal nucleus caudalis (Sp5C). We observed that the PD-1 antibody significantly inhibited mechanical hypersensitivity and functional allodynia in acute oral cancer pain model, but enhanced mechanical hypersensitivity and functional allodynia in chronic oral cancer pain model. Moreover, we demonstrated the involvement of tumor necrosis factor alpha (TNFα) in oral cancer pain. TNFα was highly expressed in the Sp5C following the induction of such pain. Intra-Sp5C injection of the PD-1 antibody significantly decreased the expression of TNFα in the Sp5C of mice with acute or chronic cancer pain. We further observed that genetic deletion of TNFα or antagonism of its receptor blocked the effect of PD-1 antibody on acute oral cancer pain. In conclusion, PD-1 in the Sp5C can regulate oral cancer pain by altering the expression of TNFα in trigeminal nociceptive system. Further elucidation of the PD-1 signaling may identify potential targets for oral cancer pain management.