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Preclinical study with a CD40 agonist on patient-derived xenograft mice for the treatment of B-cell acute lymphoblastic leukemia

ABSTRACT: To induce leukemia in NOD/SCID/γc−/− (NSG) mice, we injected 10^5 human B-ALL cells, into the tail vein of non-irradiated mice. Two different PDX mice models were studied (PDX-1; #1 and PDX-2; #2). The InVivoMAb anti-human CD40 antibody (BE0189, clone G28.5, BioXCell) was i.v. administrated (CD40) at the dose of 1 mg/kg, the same was done with the recommended isotype (Ig) (BE0083, MOPC-21, BioXCell). We administrated antibodies, at days 15 and 25. At day 35, when mice developed leukemia, B-ALL cells were purified from the BM of PDX-mice, with magnetic beads-conjugated to human CD45 antibodies. Three mice per condition were tested (replicat 1 to 3; mice m1 to m3).

INSTRUMENT(S): Bruker Daltonics timsTOF series

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): B Cell

DISEASE(S): Acute Leukemia

SUBMITTER: Guillaume CHEVREUX

LAB HEAD: Quéré Ronan

PROVIDER: PXD047749 | Pride | 2024-10-10

REPOSITORIES: Pride

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			Action	DRS
	2311003_CD40_PDX-1_replicat1_S1-C7_1_6375.d.refined.mgf	Mgf
	2311003_CD40_PDX-1_replicat1_S1-C7_1_6375.d.zip	Other
	2311003_CD40_PDX-1_replicat2_S1-D3_1_6383.d.refined.mgf	Mgf
	2311003_CD40_PDX-1_replicat2_S1-D3_1_6383.d.zip	Other
	2311003_CD40_PDX-1_replicat3_S1-D11_1_6391.d.refined.mgf	Mgf

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Project description:Background & Aims: Cholangiocarcinomas (CCAs), heterogeneous biliary tumors with dismal prognosis, lack accurate early-diagnostic methods, especially important for individuals at high-risk (i.e., primary sclerosing cholangitis (PSC)). Here, we searched for protein biomarkers in serum extracellular vesicles (EVs). Methods: EVs from patients with isolated PSC (n=45), concomitant PSC-CCA (n=42), PSC who developed CCA during follow-up (PSC to CCA; n=25), CCAs from non-PSC etiology (n=56), hepatocellular carcinoma (n=34) and healthy individuals (n=55) were characterized by mass-spectrometry. Diagnostic biomarkers of PSC-CCA, non-PSC CCA or CCAs regardless etiology (pan-CCAs) were defined, and their expression was evaluated in human organs/tissues and within CCA tumors at single-cell level. Prognostic EV-biomarkers for CCA were investigated. Results: High-throughput proteomics identified candidate diagnostic biomarkers for PSC-CCA, non-PSC CCA or pan-CCA, as well as and for differential diagnosis of intrahepatic CCA and HCC, that were cross-validated by ELISA using total serum. Machine learning logit modelling disclosed CRP/FRIL/Fibrinogen algorithm with diagnostic value for early-stage PSC-CCA vs isolated PSC (AUC=0.944; OR=82.0), overpowering CA19-9 (AUC=0.735; OR=9.3). An algorithm combining CRP/VWF/PIGR/ /Fibrinogen allowed the diagnosis of early-stage non-PSC CCAs compared to healthy individuals (AUC=0.999; OR=1115). Noteworthy, levels of Fibrinogen/CRP/PIGR/FRIL showed predictive capacity for CCA development in patients with PSC before clinical evidences of malignancy. Multi-organ transcriptomic analysis revealed that serum EV-biomarkers were mostly expressed in hepatobiliary tissues, and scRNA-seq and immunofluorescence analysis of CCA tumors showed their presence mainly in malignant cholangiocytes. Multivariable analysis unveiled EVprognostic biomarkers independent to clinical features, with COMP/GNAI2/CFAI and ACTN1/MYCT1/PF4V associated negatively or positively to patients’ survival, respectively. Conclusions: Serum EVs contain protein biomarkers for the prediction, early diagnosis and prognosis estimation of CCA, representing a novel tumor cell-derived liquid biopsy for personalized medicine.

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Preclinical study with a CD40 agonist on patient-derived xenograft mice for the treatment of B-cell acute lymphoblastic leukemia

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