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The effects of combined chemotherapy and anti-PD-1 treatment on peripheral neuropathy and neuroinflammation in mice.

ABSTRACT
A modern approach for cancer treatment is the use of immunotherapy, and particularly immune checkpoint inhibitors (ICIs), such as anti-programmed cell death protein 1 (PD-1), alone and in combination with chemotherapy. The PD-1 pathway plays a crucial role in inhibiting immune responses and recently has been shown to modulate neuronal activity. However, the impact of PD-1 blockade on the development of chemotherapy-induced peripheral neuropathy is currently unknown. In this study, we show that C57BL/6 mice treated with the chemotherapeutic drug paclitaxel or co-therapy (paclitaxel and anti-PD-1), but not with anti-PD-1 alone, exhibited increased mechanical sensitivity of the hindpaw. Both chemotherapy and immunotherapy caused a reduction in neurite outgrowth of DRG explants derived from treated mice, whilst only paclitaxel reduced the neurite outgrowth following direct in vitro treatment. Mice treated with anti-PD-1 or co-therapy exhibited distinct T cell changes in the lymph nodes and increased T cell infiltration into the DRG. Mice treated with paclitaxel or co-therapy had increased macrophage presence in the DRG, and all treated groups presented an altered expression of microglia markers in the dorsal horn of the spinal cord. We conclude that combining anti-PD-1 immunotherapy with paclitaxel does not increase the severity of paclitaxel-induced peripheral neuropathy. However, since anti-PD-1 treatment caused significant changes in DRG and spinal cord immunity, caution is warranted when considering ICIs therapy in patients with a high risk of developing neuropathy.