The effect of immunotherapy PD-1 blockade on acute bone cancer pain: Insights from transcriptomic and microbiomic profiling.

INTRODUCTION

The skeletal system ranks as the third most common site for cancer metastasis, often leading to pain with nociceptive and neuropathic features. Programmed cell death protein 1 (PD-1)-targeting therapeutic antibodies offer effective cancer treatment but can cause treatment-related acute pain. Understanding the mechanisms of this pain and identifying potential interventions is still a challenge.

METHODS

A murine model of bone cancer pain was established using Lewis lung carcinoma (LLC) cells, followed by intravenous administration of nivolumab, a human anti-PD-1 monoclonal antibody. Pain thresholds were measured, and micro-CT images of the skeletal system were obtained. High-throughput sequencing of the spinal cord/colon transcriptome during the acute phase of bone cancer pain and gut microbiota analysis at the end of the treatment were performed. Immunofluorescence staining and western blot experiments assessed spinal cord microglia activation and acute pain-associated molecules.

RESULTS

PD-1 inhibition with nivolumab protected against bone degradation initiated by LLC cell administration but consistently induced acute pain during nivolumab treatment. Spinal cord and colon transcriptomics revealed an immunopathological pattern during tumor progression and the acute pain phase, with notable changes in interleukin and S100 gene families. Gut microbiota analysis post-immunotherapy showed a decline in beneficial bacteria associated with short-chain fatty acid (SCFA) production. Activation of spinal cord microglia and enhanced glycolytic metabolism were confirmed as key factors in inducing acute pain following immunotherapy.

CONCLUSIONS

This study reveals that nivolumab induces acute pain by activating microglia and enhancing glycolytic metabolism in the treatment of bone cancer and uncovers connections between transcriptomic changes, gut microbiota, and acute pain following immune checkpoint blockade (ICB) treatment. It offers novel insights into the relationship between immune checkpoint blockade therapies and pain management.