PXD047604

PXD047604 is an original dataset announced via ProteomeXchange.

Title	Impact of PD1/PD-L1 Inhibition on Bone Remodeling: a Prospective Clinical Study and ex-vivo Validation.
Description	Background Skeletal morbidity in cancer patients has a major impact on 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 (ICI) on the skeleton are still poorly defined. Here, we initiated a comprehensive investigation of the impact of ICI on bone turnover by longitudinal assessment of bone turnover markers (BTM) in cancer patients and by validation in a novel bioengineered 3D model of bone remodeling. Methods Serum markers of bone resorption (C-terminal telopeptide, CTX) and formation (procollagen type I N-propeptide, PINP; and osteocalcin, OCN) were measured before each ICI application (PD1 inhibitors, PD1i or PD-L1 inhibitors, PD1i) for 6 months or until disease progression in patients with advanced cancer and no evidence of bone metastases. To validate the in vivo results, we evaluated osteoclast (OC) and osteoblast (OB) differentiation upon treatment with ICI. In addition, their effect on bone remodeling was assessed by immunohistochemistry, immunofluorescence and proteomics analysis in a dynamic 3D model of the bone multicellular unit (BMU). Results The longitudinal assessment of BTM revealed a significant decrease in CTX levels after 3 weeks, followed by a return to baseline levels within 3 months. In contrast, serum levels of PINP and OCN gradually increased from baseline to the last postbaseline assessment. In vitro, ICI 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 novel bioengineered 3D bone model, which enables the simultaneous differentiation of OB and OC precursor cells, we confirmed the uncoupling of the OC/OB activity upon ICI treatment by demonstrating impaired OC maturation along with increased OB differentiation. Conclusion Our study indicates that the inhibition of the PD1/PD-L1 signaling axis interferes with the OB/OC coupling of bone turnover and may potentially exert a protective effect on bone by impairing the differentiation OCs and indirectly promoting osteogenesis.
HostingRepository	PRIDE
AnnounceDate	2024-05-21
AnnouncementXML	Submission_2024-05-21_09:21:14.638.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Benjamin Neuditschko
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	iodoacetamide derivatized residue
Instrument	Orbitrap Eclipse

Revision	Datetime	Status	ChangeLog Entry
0	2023-12-07 02:05:54	ID requested
⏵ 1	2024-05-21 09:21:15	announced

Gassner T, Chittilappilly C, Pirich T, Neuditschko B, Hackner K, Lind J, Aksoy O, Graichen U, Klee S, Herzog F, Wiesner C, Errhalt P, Pecherstorfer M, Podar K, Vallet S, Favorable impact of PD1/PD-L1 antagonists on bone remodeling: an exploratory prospective clinical study and ex vivo validation. J Immunother Cancer, 12(5):(2024) [pubmed]

10.1136/jitc-2023-008669;

submitter keyword: bone remodeling

immune-checkpoint inhibitors

3D model

data-independent acquisition

Franz Herzog
contact affiliation	Institute Krems Bioanalytics, IMC University of Applied Sciences, 3500 Krems, Austria
contact email	franz.herzog@fh-krems.ac.at
lab head
Benjamin Neuditschko
contact affiliation	Institute Krems Bioanalytics, IMC University of Applied Sciences Krems, 3500 Krems, Austria
contact email	benjamin.neuditschko@fh-krems.ac.at
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2024/05/PXD047604

PRIDE project URI

• PRIDE
  1. PXD047604
     1. Label: PRIDE project
     2. Name: Impact of PD1/PD-L1 Inhibition on Bone Remodeling: a Prospective Clinical Study and ex-vivo Validation.