Immunoregulatory roles of versican proteolysis in the myeloma microenvironment.
Myeloma immunosurveillance remains incompletely understood. We have demonstrated proteolytic processing of the matrix proteoglycan, versican (VCAN), in myeloma tumors. Whereas intact VCAN exerts tolerogenic activities through Toll-like receptor 2 (TLR2) binding, the immunoregulatory consequences of VCAN proteolysis remain unknown. Here we show that human myeloma tumors displaying CD8(+) infiltration/aggregates underwent VCAN proteolysis at a site predicted to generate a glycosaminoglycan-bereft N-terminal fragment, versikine Myeloma-associated macrophages (MAMs), rather than tumor cells, chiefly produced V1-VCAN, the precursor to versikine, whereas stromal cell-derived ADAMTS1 was the most robustly expressed VCAN-degrading protease. Purified versikine induced early expression of inflammatory cytokines interleukin 1β (IL-1β) and IL-6 by human myeloma marrow-derived MAMs. We show that versikine signals through pathways both dependent and independent of Tpl2 kinase, a key regulator of nuclear factor κB1-mediated MAPK activation in macrophages. Unlike intact VCAN, versikine-induced Il-6 production was partially independent of Tlr2. In a model of macrophage-myeloma cell crosstalk, versikine induced components of "T-cell inflammation," including IRF8-dependent type I interferon transcriptional signatures and T-cell chemoattractant CCL2. Thus the interplay between stromal cells and myeloid cells in the myeloma microenvironment generates versikine, a novel bioactive damage-associated molecular pattern that may facilitate immune sensing of myeloma tumors and modulate the tolerogenic consequences of intact VCAN accumulation. Therapeutic versikine administration may potentiate T-cell-activating immunotherapies.
Division of Hematology/Oncology, Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI; University of Wisconsin Carbone Cancer Center, Madison, WI;
Chelsea
C
Hope
Department of Biomedical Engineering, Cleveland Clinic Lerner Research Institute, Cleveland Clinic, Cleveland, OH;
Simon
S
Foulcer
Division of Hematology/Oncology, Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI; University of Wisconsin Carbone Cancer Center, Madison, WI;
Justin
J
Jagodinsky
Division of Hematology/Oncology, Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI; University of Wisconsin Carbone Cancer Center, Madison, WI;
Sarah X
SX
Chen
Division of Hematology/Oncology, Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI; University of Wisconsin Carbone Cancer Center, Madison, WI;
Jeffrey L
JL
Jensen
Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI;
Sanjay
S
Patel
Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI;
Catherine
C
Leith
Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupolis, Greece; and.
Ioanna
I
Maroulakou
Division of Hematology/Oncology, Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI; University of Wisconsin Carbone Cancer Center, Madison, WI;
Natalie
N
Callander
Department of Oncology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI.
Shigeki
S
Miyamoto
Division of Hematology/Oncology, Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI; University of Wisconsin Carbone Cancer Center, Madison, WI;
Peiman
P
Hematti
Department of Biomedical Engineering, Cleveland Clinic Lerner Research Institute, Cleveland Clinic, Cleveland, OH;
Suneel S
SS
Apte
Division of Hematology/Oncology, Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI; University of Wisconsin Carbone Cancer Center, Madison, WI;
Fotis
F
Asimakopoulos
D000067531:Alarmins / Q000378:metabolism; D000818:Animals; D006801:Humans; D056747:Immunomodulation; D050835:Interferon Regulatory Factors / Q000378:metabolism; D009101:Multiple Myeloma / Q000276:immunology* / Q000473:pathology*; D059748:Proteolysis; D014158:Transcription, Genetic; D059016:Tumor Microenvironment; D053675:Versicans / Q000378:metabolism*; D000099185:Interferon Regulatory Factor-8
D000067531:Alarmins; D050835:Interferon Regulatory Factors; D053675:Versicans; D000099185:Interferon Regulatory Factor-8