Dataset Information

Multiplex PRM quantitation of CD8a, CD4, LAG3, PD1, PD-L1 and PD-L2

ABSTRACT: Immuno-LC-PRM assay was developed to simultaneously quantify the expression levels of six immune markers (CD8A, CD4, LAG3, PD1, PD-L1 and PD-L2) using as little as 1-2 mg of fresh frozen tissue.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): T Cell, Lymph Node

DISEASE(S): Cervix Carcinoma

SUBMITTER: Yashu Liu

LAB HEAD: Yashu Liu

PROVIDER: PXD011152 | Pride | 2018-10-04

REPOSITORIES: Pride

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Publications

Multiplex Immuno-Liquid Chromatography-Mass Spectrometry-Parallel Reaction Monitoring (LC-MS-PRM) Quantitation of CD8A, CD4, LAG3, PD1, PD-L1, and PD-L2 in Frozen Human Tissues.

Zhang Qian Q Salzler Robert R Dore Anthony A Yang Janice J Ma Dangshe D Olson William C WC Liu Yashu Y

Journal of proteome research 20181011 11

The immune status of tumors critically influences their responsiveness to PD1 blockades and other immune-based therapies. Programmed death ligand 1 (PD-L1) immunohistochemistry (IHC) is a clinically validated predictive biomarker of response to checkpoint-inhibitor therapy in a limited number of clinical settings but is poorly predictive in most. With emerging evidence that multiple pathways and immune-checkpoint proteins may coordinately contribute to the adaptive immune resistance, the identif ...[more]

PMID: 30277784

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Project 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.

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