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


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Abstract

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 the present 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 intra-epidermal 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 prior to 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 naïve WT 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 (TCR). 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.

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