Favorable impact of PD1/PD-L1 antagonists on bone remodeling: an exploratory prospective clinical study and ex vivo validation.
Immune Checkpoint Inhibitor
Monocyte
Solid tumor
Stem cell
Treatment related adverse event - trAE
Journal
Journal for immunotherapy of cancer
ISSN: 2051-1426
Titre abrégé: J Immunother Cancer
Pays: England
ID NLM: 101620585
Informations de publication
Date de publication:
03 May 2024
03 May 2024
Historique:
accepted:
19
04
2024
medline:
4
5
2024
pubmed:
4
5
2024
entrez:
3
5
2024
Statut:
epublish
Résumé
Skeletal morbidity in patients with cancer has a major impact on the quality of life, and preserving bone health while improving outcomes is an important goal of modern antitumor treatment strategies. Despite their widespread use in early disease stages, the effects of immune checkpoint inhibitors (ICIs) on the skeleton are still poorly defined. Here, we initiated a comprehensive investigation of the impact of ICIs on bone health by longitudinal assessment of bone turnover markers in patients with cancer and by validation in a novel bioengineered 3D model of bone remodeling. An exploratory longitudinal study was conducted to assess During the first month of treatment, CTX levels decreased sharply but transiently. In contrast, we observed a delayed increase of serum levels of PINP and OCN after 4 months of therapy. In vitro, ICIs impaired the maturation of preosteoclasts by inhibiting STAT3/NFATc1 signaling but not JNK, ERK, and AKT while lacking any direct effect on osteogenesis. However, using our bioengineered 3D bone model, which enables the simultaneous differentiation of OB and OC precursor cells, we confirmed the uncoupling of the OC/OB activity on exposure to ICIs by demonstrating impaired OC maturation along with increased OB differentiation. Our study indicates that the inhibition of the PD1/PD-L1 signaling axis interferes with bone turnover and may exert a protective effect on bone by indirectly promoting osteogenesis.
Sections du résumé
BACKGROUND
BACKGROUND
Skeletal morbidity in patients with cancer has a major impact on the quality of life, and preserving bone health while improving outcomes is an important goal of modern antitumor treatment strategies. Despite their widespread use in early disease stages, the effects of immune checkpoint inhibitors (ICIs) on the skeleton are still poorly defined. Here, we initiated a comprehensive investigation of the impact of ICIs on bone health by longitudinal assessment of bone turnover markers in patients with cancer and by validation in a novel bioengineered 3D model of bone remodeling.
METHODS
METHODS
An exploratory longitudinal study was conducted to assess
RESULTS
RESULTS
During the first month of treatment, CTX levels decreased sharply but transiently. In contrast, we observed a delayed increase of serum levels of PINP and OCN after 4 months of therapy. In vitro, ICIs impaired the maturation of preosteoclasts by inhibiting STAT3/NFATc1 signaling but not JNK, ERK, and AKT while lacking any direct effect on osteogenesis. However, using our bioengineered 3D bone model, which enables the simultaneous differentiation of OB and OC precursor cells, we confirmed the uncoupling of the OC/OB activity on exposure to ICIs by demonstrating impaired OC maturation along with increased OB differentiation.
CONCLUSION
CONCLUSIONS
Our study indicates that the inhibition of the PD1/PD-L1 signaling axis interferes with bone turnover and may exert a protective effect on bone by indirectly promoting osteogenesis.
Identifiants
pubmed: 38702145
pii: jitc-2023-008669
doi: 10.1136/jitc-2023-008669
pii:
doi:
Substances chimiques
Immune Checkpoint Inhibitors
0
Programmed Cell Death 1 Receptor
0
B7-H1 Antigen
0
CD274 protein, human
0
PDCD1 protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
Déclaration de conflit d'intérêts
Competing interests: KP has received speaker’s honoraria from Celgene, Amgen Inc, and Janssen Pharmaceuticals; consultancy fees from Celgene, Takeda, Janssen Pharmaceuticals, and Amgen; and research support from Roche Pharmaceuticals. SV has received speaker's honoraria from Bristol Myers Squibb, Pfizer, MSD, and Merck; consultancy fees from Roche, MSD, EUSA Pharma, and Merck; and travel support from Pfizer, Roche, Pierre Fabre, and Angelini.