PD-1 blockade inhibits osteoclast formation and murine bone cancer pain

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 can...

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Veröffentlicht in:	The Journal of clinical investigation Jg. 130; H. 7; S. 3603 - 3620
Hauptverfasser:	Wang, Kaiyuan, Gu, Yun, Liao, Yihan, Bang, Sangsu, Donnelly, Christopher R., Chen, Ouyang, Tao, Xueshu, Mirando, Anthony J., Hilton, Matthew J., Ji, Ru-Rong
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	United States American Society for Clinical Investigation 01.07.2020
Schlagworte:	Animals Antibodies Apoptosis Biomedical research Bone cancer Bone growth Bone Neoplasms - drug therapy Bone Neoplasms - genetics Bone Neoplasms - metabolism Bone Neoplasms - pathology 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 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 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 Neuroscience Bone disease Pain Cancer Cell Biology
ISSN:	0021-9738, 1558-8238, 1558-8238
Online-Zugang:	Volltext
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Zusammenfassung:	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.
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Authorship note: KW and YG share first authorship. RRJ and KW share senior authorship.
ISSN:	0021-9738 1558-8238 1558-8238
DOI:	10.1172/JCI133334