Related Experiment Video
Updated: Dec 20, 2025
Osteoclast Derivation from Mouse Bone Marrow
Published on: November 6, 2014
PD-1 blockade inhibits osteoclast formation and murine bone cancer pain
Kaiyuan Wang1, Yun Gu1, Yihan Liao2,3
1Center for Translational Pain Medicine, Department of Anesthesiology.
Abstract:
Emerging immune therapy, such as with the anti-programmed cell death-1 (anti-PD-1) monoclonal antibody nivolumab, has shown efficacy in tumor suppression. Patients with terminal cancer suffer from cancer pain as a result of bone metastasis and bone destruction, but how PD-1 blockade affects bone cancer pain remains unknown. Here, we report that mice lacking Pdcd1 (Pd1-/-) demonstrated remarkable protection against bone destruction induced by femoral inoculation of Lewis lung cancer cells. Compared with WT mice, Pd1-/- mice exhibited increased baseline pain sensitivity, but the development of bone cancer pain was compromised in Pd1-/- mice. Consistently, these beneficial effects in Pd1-/- mice were recapitulated by repeated i.v. applications of nivolumab in WT mice, even though nivolumab initially increased mechanical and thermal pain. Notably, PD-1 deficiency or nivolumab treatment inhibited osteoclastogenesis without altering tumor burden. PD-L1 and CCL2 are upregulated within the local tumor microenvironment, and PD-L1 promoted RANKL-induced osteoclastogenesis through JNK activation and CCL2 secretion. Bone cancer upregulated CCR2 in primary sensory neurons, and CCR2 antagonism effectively reduced bone cancer pain. Our findings suggest that, despite a transient increase in pain sensitivity following each treatment, anti-PD-1 immunotherapy could produce long-term benefits in preventing bone destruction and alleviating bone cancer pain by suppressing osteoclastogenesis.
Insights
Anti-programmed cell death-1 (anti-PD-1) immunotherapy, like nivolumab, may alleviate bone cancer pain. This therapy inhibits bone destruction and osteoclastogenesis, offering long-term benefits despite initial pain increases.
Area of Science:
- Immunology
- Oncology
- Pain Research
Background:
- Immune checkpoint inhibitors, such as anti-PD-1 therapy, show promise in cancer treatment.
- Bone metastasis causes significant pain in terminal cancer patients.
- The effect of PD-1 blockade on bone cancer pain is not well understood.
Purpose of the Study:
- To investigate the impact of PD-1 blockade on bone destruction and cancer pain.
- To elucidate the mechanisms by which PD-1 signaling influences osteoclastogenesis and pain pathways.
Main Methods:
- Utilized genetically modified mice (Pd1-/-) and wild-type mice treated with nivolumab.
- Administered Lewis lung cancer cells to induce bone metastasis and pain.
- Analyzed osteoclastogenesis, tumor burden, and pain sensitivity (mechanical and thermal).
- Investigated the roles of PD-L1, CCL2, and CCR2 in the tumor microenvironment and sensory neurons.
Main Results:
- Pd1-/- mice showed protection against bone destruction and compromised bone cancer pain development.
- Nivolumab treatment in wild-type mice mimicked these protective effects, despite transient pain increases.
- PD-1 blockade inhibited osteoclastogenesis without affecting tumor burden.
- PD-L1 promoted osteoclastogenesis via JNK activation and CCL2 secretion; CCR2 antagonism reduced bone cancer pain.
Conclusions:
- Anti-PD-1 immunotherapy can prevent bone destruction and alleviate bone cancer pain.
- The mechanism involves suppressing osteoclastogenesis and modulating pain signaling pathways.
- This approach offers potential long-term benefits for cancer pain management.
