Effects of combined chemotherapy and anti-programmed cell death protein 1 treatment on peripheral neuropathy and neuroinflammation in mice.

ABSTRACT

ABSTRACT A modern approach for cancer treatment is the use of immunotherapy, and particularly immune checkpoint inhibitors, 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 cotherapy (paclitaxel and anti-PD-1), but not with anti-PD-1 alone, exhibited increased mechanical sensitivity of the hind paw. Both chemotherapy and immunotherapy caused a reduction in neurite outgrowth of dorsal root ganglion (DRG) explants derived from treated mice, whereas only paclitaxel reduced the neurite outgrowth after direct in vitro treatment. Mice treated with anti-PD-1 or cotherapy exhibited distinct T-cell changes in the lymph nodes and increased T-cell infiltration into the DRG. Mice treated with paclitaxel or cotherapy 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, because anti-PD-1 treatment caused significant changes in DRG and spinal cord immunity, caution is warranted when considering immune checkpoint inhibitors therapy in patients with a high risk of developing neuropathy.