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PD-L1 on pain

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Sci. Signal.  18 Jul 2017:
Vol. 10, Issue 488, eaao3722
DOI: 10.1126/scisignal.aao3722

As well as being an immunosuppressive checkpoint, the tumor-associated cell surface molecule PD-L1 suppresses pain signaling in sensory neurons.

Chronic pain is a common symptom in patients with advanced cancer, in part due to the secretion of pronociceptive factors from tumor cells. However, early-stage tumors do not typically cause pain, and recently it was observed that the secretion of a chemokine from early-stage pancreatic tumors suppresses pain signaling, which facilitates stealthy tumor growth. Through contact between programmed cell death ligand 1 (PD-L1) on tumor cells and its receptor, PD-1, on immune cells, tumors also suppress immune cell–mediated detection. Immunotherapies inhibiting the PD-L1–PD-1 axis are effective in some cancer patients. Now, Chen et al. show that PD-L1 also suppresses pain signaling (see also Hirth et al.). The authors observed that PD-1 was expressed in various tissues, particularly in the spinal cord and sensory neurons of the dorsal root ganglion (DRG). In mice, administration of PD-L1 dampened basal and chemically or mechanically evoked pain. Various assays in mice and cultured DRG neurons revealed that the analgesic effects of PD-L1 were mediated by its interaction with PD-1 and subsequent activation of the phosphatase SHP-1, which suppressed the activity of Na2+ channels and enhanced the activity of K+ channels, ultimately hyperpolarizing neurons and reducing their excitability. Inhibiting PD-1 in tumor-bearing mice elicited allodynia and unprovoked pain, indicating that tumors may use PD-L1 as a way to inhibit both immune- and pain-mediated early detection. Furthermore, pain may be an unfortunate side effect of PD-1–targeted immunotherapy in cancer patients. The findings uncover a previously unknown regulator of pain signaling. Although they suggest that activating the PD-L1–PD-1 axis may be effective in treating chronic pain in patients, the associated risks of infection and cancer (and, given the presence of PD-1 in other tissues, potentially as-yet-unknown consequences) would need to be carefully considered and monitored in patients.

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