The Journal of clinical investigation, 2020-07, Vol.130 (7), p.3603-3620
2020
Details
- Autor(en) / Beteiligte
- Titel
- PD-1 blockade inhibits osteoclast formation and murine bone cancer pain
- Ist Teil von
- The Journal of clinical investigation, 2020-07, Vol.130 (7), p.3603-3620
- Ort / Verlag
- United States: American Society for Clinical Investigation
- Erscheinungsjahr
- 2020
- Link zum Volltext
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0021-9738eISSN: 1558-8238DOI: 10.1172/jci133334Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7324182
- Format
- –
- Schlagworte
- Animals, Antibodies, Apoptosis, Biomedical research, Bone cancer, Bone growth, Bone Neoplasms - drug therapy, Bone Neoplasms - genetics, Bone Neoplasms - metabolism, Bone Neoplasms - pathology, Cancer, Cancer metastasis, Cancer pain, Cancer Pain - drug therapy, Cancer Pain - genetics, Cancer Pain - metabolism, Cancer Pain - pathology, Cancer prevention, Cancer therapies, Carcinoma, Lewis Lung - drug therapy, Carcinoma, Lewis Lung - genetics, Carcinoma, Lewis Lung - metabolism, Carcinoma, Lewis Lung - pathology, Care and treatment, CCR2 protein, Cell death, Cold, Comparative analysis, Development and progression, Female, Fractures, Gender differences, Immunotherapy, Inoculation, Lung cancer, Melanoma, Metastases, Metastasis, Mice, Mice, Knockout, Monoclonal antibodies, Monocyte chemoattractant protein 1, Neoplasm Proteins - antagonists & inhibitors, Neoplasm Proteins - genetics, Neoplasm Proteins - metabolism, Nivolumab, Nivolumab - pharmacology, Osteoclastogenesis, Osteoclasts - metabolism, Osteoclasts - pathology, Pain, Pain management, PD-1 protein, PD-L1 protein, Prevention, Programmed Cell Death 1 Receptor - antagonists & inhibitors, Programmed Cell Death 1 Receptor - genetics, Programmed Cell Death 1 Receptor - metabolism, Rodents, Sensory neurons, Skin cancer, Targeted cancer therapy, TRANCE protein, Tumor suppression