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Cisplatin educates CD8+ T cells to prevent and resolve chemotherapy-induced peripheral neuropathy in mice

Laumet, Geoffroy; Edralin, Jules D.; Dantzer, Robert; Heijnen, Cobi J.; Kavelaars, Annemieke*

doi: 10.1097/j.pain.0000000000001512
Research Paper

The mechanisms responsible for the persistence of chemotherapy-induced peripheral neuropathy (CIPN) in a significant proportion of cancer survivors are still unknown. Our previous findings show that CD8+ T cells are necessary for the resolution of paclitaxel-induced mechanical allodynia in male mice. In this study, we demonstrate that CD8+ T cells are not only essential for resolving cisplatin-induced mechanical allodynia, but also to normalize spontaneous pain, numbness, and the reduction in intraepidermal nerve fiber density in male and female mice. Resolution of CIPN was not observed in Rag2−/− mice that lack T and B cells. Reconstitution of Rag2−/− mice with CD8+ T cells before cisplatin treatment normalized the resolution of CIPN. In vivo education of CD8+ T cells by cisplatin was necessary to induce resolution of CIPN in Rag2−/− mice because adoptive transfer of CD8+ T cells from naive wild-type mice to Rag2−/− mice after completion of chemotherapy did not promote resolution of established CIPN. The CD8+ T-cell-dependent resolution of CIPN does not require epitope recognition by the T-cell receptor. Moreover, adoptive transfer of cisplatin-educated CD8+ T cells to Rag2−/− mice prevented CIPN development induced by either cisplatin or paclitaxel, indicating that the activity of the educated CD8+ T is not cisplatin specific. In conclusion, resolution of CIPN requires in vivo education of CD8+ T cells by exposure to cisplatin. Future studies should examine whether ex vivo CD8+ T cell education could be applied as a therapeutic strategy for treating or preventing CIPN in patients.

We show that resolution of chemotherapy-induced peripheral neuropathy (CIPN) after cisplatin treatment is an active process that includes a critical role for CD8+ T cells in the resolution of allodynia, spontaneous pain, numbness, and reduction of intraepidermal nerve fiber density, regardless of sex. Moreover, CD8+ T cells need to be educated by cisplatin to resolve established CIPN. We also demonstrate that cisplatin educates CD8+ T cells, which can be used to prevent CIPN induced either by cisplatin or paclitaxel.

Department of Symptom Research, Laboratory of Neuroimmunology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States

Corresponding author. Address: Department of Symptom Research, Laboratory of Neuroimmunology, The University of Texas MD Anderson Cancer Center, Unit 384, 1515 Holcombe Blvd, Houston, TX, 77030, United States. Tel.: 713-794-5297; fax: 713-745-3475. E-mail address: (A. Kavelaars).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

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Received November 27, 2018

Received in revised form January 08, 2019

Accepted January 25, 2019

© 2019 International Association for the Study of Pain
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