Neutrophil-derived APRIL concentrated in tumor lesions by proteoglycans correlates with human B-cell lymphoma aggressiveness.
A PRoliferation-Inducing TNF Ligand (APRIL) costimulates B-cell activation. When overexpressed in mice, APRIL induces B-cell neoplasia, reminiscent of human B-cell chronic lymphoid leukemia (B-CLL). We analyzed APRIL expression in situ in human non-Hodgkin lymphomas. APRIL up-regulation was only observed in high-grade B-cell lymphomas, diffuse large B-cell lymphoma (DLBCL), and Burkitt lymphoma (BL). Up-regulation was seen in 46% and 20% of DLBCL and BL, respectively. In DLBCL, neutrophils, constitutively producing APRIL and infiltrating the tumor tissue, were the main cellular source of APRIL. Rare DLBCL cases showed a predominance of histiocytes or mesenchymal cells as APRIL source. APRIL secreted by neutrophils accumulated on tumor cells via proteoglycan binding. In addition to proteoglycans, DLBCL tumor cells expressed the APRIL signaling receptor, TACI and/or BCMA, indicating that these tumor cells are fully equipped to respond to APRIL. A retrospective clinical analysis revealed a significant correlation between high expression of APRIL in tumor lesions and decreased overall patient survival rate. Hence, APRIL produced by inflammatory cells infiltrating lymphoma lesions may increase tumor aggressiveness and affect disease outcome.
Schwaller
Juerg
J
Department of Research, University Hospital, Basel, Switzerland.
Schneider
Pascal
P
Mhawech-Fauceglia
Paulette
P
McKee
Thomas
T
Myit
Samir
S
Matthes
Thomas
T
Tschopp
Jurg
J
Donze
Olivier
O
Le Gal
Frederique-Anne
FA
Huard
Bertrand
B
D053301:B-Cell Maturation Antigen / Q000378:metabolism; D002051:Burkitt Lymphoma / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D016393:Lymphoma, B-Cell / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D008228:Lymphoma, Non-Hodgkin / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009504:Neutrophils / Q000378:metabolism*; D011379:Prognosis; D017434:Protein Structure, Tertiary; D011509:Proteoglycans / Q000378:metabolism*; D012189:Retrospective Studies; D016019:Survival Analysis; D053303:Transmembrane Activator and CAML Interactor Protein / Q000378:metabolism; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation
D053301:B-Cell Maturation Antigen; D009363:Neoplasm Proteins; D011509:Proteoglycans; C108467:TNFRSF13B protein, human; C086966:TNFRSF17 protein, human; C114631:TNFSF13 protein, human; D053303:Transmembrane Activator and CAML Interactor Protein; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13