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Papers of the Week


Papers: 10 Sep 2022 - 16 Sep 2022


2022 Sep 09


Cancer Immunol Res

Editor's Pick

PD-1/PD-L1 inhibition enhances chemotherapy-induced neuropathic pain by suppressing neuroimmune antinociceptive signaling.

Authors

Wanderley C WS, Maganin A, Adjafre B, Mendes AS, Anibal Silva C E, Quadros A U, Luiz J P M, Silva C MS, Silva NR, Oliveira FF, F Gomes F I, Restrepo J LJ, Speck-Hernandez CA, Turaça F, Silva G V L, Pigatto GR, Nakaya HI, Mota J M, Barroso-Sousa R, Alves-Filho JC, et al.
Cancer Immunol Res. 2022 Sep 09.
PMID: 36083496.

Abstract

Cytotoxic agents synergize with immune checkpoint inhibitors and improve outcomes for patients with several cancer types. Nonetheless, a parallel increase in the incidence of dose-limiting side effects, such as peripheral neuropathy, is often observed. Here, we investigated the role of the PD-1/PD-L1 axis in the modulation of paclitaxel-induced neuropathic pain. We found that human and mouse neural tissues, including the dorsal root ganglion (DRG), expressed basal levels of PD-1 and PD-L1. During the development of paclitaxel-induced neuropathy, an increase in PD-L1 expression was observed in macrophages from the DRG. This effect depended on Toll-like receptor 4 (TLR4) activation by paclitaxel. Furthermore, PD-L1 inhibited pain behavior triggered by paclitaxel or formalin in mice, suggesting that PD-1/PD-L1 signaling attenuates peripheral neuropathy development. Consistent with this, we observed that the combined use of anti-PD-L1 plus paclitaxel increased mechanical allodynia and chronic neuropathy development induced by single agents. This effect was associated with higher expression of inflammatory markers (Tnf, Il6, and Cx3cr1) in peripheral nervous tissue. Together, these results suggest that PD-1/PD-L1 inhibitors enhance paclitaxel-induced neuropathic pain by suppressing PD-1/PD-L1 antinociceptive signaling.