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

The Journal of clinical investigation, 2020-07, Vol.130 (7), p.3603-3620 [Peer Reviewed Journal]

COPYRIGHT 2020 American Society for Clinical Investigation ;COPYRIGHT 2020 American Society for Clinical Investigation ;Copyright American Society for Clinical Investigation Jul 2020 ;2020 American Society for Clinical Investigation 2020 American Society for Clinical Investigation ;ISSN: 0021-9738 ;EISSN: 1558-8238 ;DOI: 10.1172/jci133334 ;PMID: 32484460

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Title:
PD-1 blockade inhibits osteoclast formation and murine bone cancer pain
Author: Wang, Kaiyuan ; Gu, Yun ; Liao, Yihan ; Bang, Sangsu ; Donnelly, Christopher R ; Chen, Ouyang ; Tao, Xueshu ; Mirando, Anthony J ; Hilton, Matthew J ; Ji, Ru-Rong
Subjects: Animals ; Antibodies ; Apoptosis ; 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 ; CC chemokine receptors ; 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 ; Movement disorders ; 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
Is Part Of: The Journal of clinical investigation, 2020-07, Vol.130 (7), p.3603-3620
Description: 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.
Publisher: United States: American Society for Clinical Investigation
Language: English
Identifier: ISSN: 0021-9738
EISSN: 1558-8238
DOI: 10.1172/jci133334
PMID: 32484460
Source: PubMed Central (Open access)
Geneva Foundation Free Medical Journals at publisher websites
MEDLINE
Alma/SFX Local Collection
ProQuest Central

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

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