PD-1/PD-L1 Inhibition Enhances Chemotherapy-Induced Neuropathic Pain by Suppressing Neuroimmune Antinociceptive Signaling

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Wanderley, Carlos Wagner S. ; Maganin, Alexandre G. M. ; Adjafre, Beatriz ; Mendes, Atlante S. ; Silva, Conceicao Elidianne Anibal ; Quadros, Andreza Urba ; Luiz, Joao Paulo Mesquita ; Silva, Camila Meirelles S. ; Silva, Nicole R. ; Oliveira, Francisco Fabio Bezerra ; Gomes, Francisco Isaac F. ; Restrepo, Jeferson Leandro J. ; Speck-Hernandez, Cesar A. ; Turaca, Fernanda ; Silva, Gabriel Victor Lucena ; Pigatto, Glauce R. ; Nakaya, Helder I. ; Mota, Jose Mauricio ; Barroso-Sousa, Romualdo ; Alves-Filho, Jose C. ; Cunha, Thiago M. ; Cunha, Fernando Q.

• Tipo de documento: Artigo Científico
• Fonte: CANCER IMMUNOLOGY RESEARCH; v. 10, n. 11, p. 10-pg., 2022-11-01.

Resumo

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 programmed cell death-1 (PD-1)/ programmed death-ligand 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 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 neu-ropathy 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 inflam-matory 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. (AU)

• Processo FAPESP: 13/08216-2 - CPDI - Centro de Pesquisa em Doenças Inflamatórias
• Beneficiário: Fernando de Queiroz Cunha
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• Processo FAPESP: 17/25308-9 - Papel do ácido lático na resistência aos inibidores de checkpoint (anti-PD-1/PD-L1) utilizados na imunoterapia contra o câncer
• Beneficiário: Carlos Wagner de Souza Wanderley
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado