(369) Cell Specific Role of HDAC6 in Chemotherapy-Induced Mechanical Allodynia and Loss of Intraepidermal Nerve Fibers

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) is a serious healthcare issue that can impair cancer treatment and reduce quality of life for cancer survivors. Currently there is no FDA-approved medication to manage CIPN, emphasizing the urgent need to identify novel mechanism-based interventions for CIPN. Histone deacetylase 6 (HDAC6) is an attractive target, given its pathogenic role in both cancer and neurodegenerative diseases. We show that cisplatin enhances HDAC6 expression and decreases acetylation of the HDAC6 substrate α-tubulin in the dorsal root ganglion (DRG). Pharmacological inhibition of HDAC6 with ACY-1215, an HDAC6 inhibitor that is currently in clinical trials as add-on cancer therapy, prevented cisplatin-induced mechanical allodynia, loss of intraepidermal nerve fibers (IENFs), and mitochondrial dysfunction in the DRG neurons and peripheral nerves in male and female mice. Genetic deletion of HDAC6 also protected against all CIPN signs. Interestingly, cell specific deletion of HDAC6 in Advilin-positive sensory neurons prevented loss of IENFs and mitochondrial deficits in the peripheral nerves, but not mechanical allodynia or DRG neuronal mitochondrial dysfunction. We previously showed that T cells are required for spontaneous resolution of mechanical allodynia in CIPN. Here we assessed the contribution of T cells to the beneficial effects of HDAC6 inhibition. HDAC6 inhibition during chemotherapy in T cell deficient Rag2−/− mice also prevented IENF loss and mitochondrial dysfunction in the peripheral nerves, but not mechanical allodynia or DRG mitochondrial deficits. Reconstitution with T cells normalized the protective effects of ACY-1215. Adoptive transfer of HDAC6 deficient T cells to Rag2−/− mice failed to protect against CIPN, indicating targeting HDAC6 in T cells alone was not sufficient. Taken together, our findings identify cell specific mechanisms for the protective effects of HDAC6 inhibition on cisplatin-induced mechanical allodynia and IENF loss. Our findings also strengthen the rationale for using HDAC6 inhibitors like ACY-1215 for CIPN prevention.