TPL2 kinase regulates the inflammatory milieu of the myeloma niche.
Targeted modulation of microenvironmental regulatory pathways may be essential to control myeloma and other genetically/clonally heterogeneous cancers. Here we report that human myeloma-associated monocytes/macrophages (MAM), but not myeloma plasma cells, constitute the predominant source of interleukin-1β (IL-1β), IL-10, and tumor necrosis factor-α at diagnosis, whereas IL-6 originates from stromal cells and macrophages. To dissect MAM activation/cytokine pathways, we analyzed Toll-like receptor (TLR) expression in human myeloma CD14(+) cells. We observed coregulation of TLR2 and TLR6 expression correlating with local processing of versican, a proteoglycan TLR2/6 agonist linked to carcinoma progression. Versican has not been mechanistically implicated in myeloma pathogenesis. We hypothesized that the most readily accessible target in the versican-TLR2/6 pathway would be the mitogen-activated protein 3 (MAP3) kinase, TPL2 (Cot/MAP3K8). Ablation of Tpl2 in the genetically engineered in vivo myeloma model, Vκ*MYC, led to prolonged disease latency associated with plasma cell growth defect. Tpl2 loss abrogated the "inflammatory switch" in MAM within nascent myeloma lesions and licensed macrophage repolarization in established tumors. MYC activation/expression in plasma cells was independent of Tpl2 activity. Pharmacologic TPL2 inhibition in human monocytes led to dose-dependent attenuation of IL-1β induction/secretion in response to TLR2 stimulation. Our results highlight a TLR2/6-dependent TPL2 pathway as novel therapeutic target acting nonautonomously through macrophages to control myeloma progression.
Department of Medicine, Division of Hematology/Oncology, 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 Medicine, Division of Hematology/Oncology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI; University of Wisconsin Carbone Cancer Center, Madison, WI;
Samuel J
SJ
Ollar
University of Wisconsin Carbone Cancer Center, Madison, WI;
Erika
E
Heninger
Department of Medicine, Division of Hematology/Oncology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI; University of Wisconsin Carbone Cancer Center, Madison, WI;
Ellen
E
Hebron
Department of Medicine, Division of Hematology/Oncology, 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 Medicine, Division of Hematology/Oncology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI; University of Wisconsin Carbone Cancer Center, Madison, WI;
Jaehyup
J
Kim
Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupolis, Greece;
Ioanna
I
Maroulakou
University of Wisconsin Carbone Cancer Center, Madison, WI; Department of Oncology, University of Wisconsin-Madison, Madison, WI;
Shigeki
S
Miyamoto
Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI; and.
Catherine
C
Leith
Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI; and.
David T
DT
Yang
Department of Medicine, Division of Hematology/Oncology, 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 Medicine, Division of Hematology/Oncology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI; University of Wisconsin Carbone Cancer Center, Madison, WI;
Peiman
P
Hematti
Mayo Clinic-Scottsdale, Scottsdale, AZ.
Marta
M
Chesi
Mayo Clinic-Scottsdale, Scottsdale, AZ.
P Leif
PL
Bergsagel
Department of Medicine, Division of Hematology/Oncology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI; University of Wisconsin Carbone Cancer Center, Madison, WI;
Fotis
F
Asimakopoulos
D000818:Animals; D016207:Cytokines / Q000032:analysis / Q000276:immunology; D055808:Drug Discovery; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053583:Interleukin-1beta / Q000032:analysis / Q000276:immunology; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D008264:Macrophages / Q000276:immunology / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009101:Multiple Myeloma / Q000175:diagnosis / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000819:agonists; D051216:Toll-Like Receptor 6 / Q000235:genetics / Q000276:immunology; D059016:Tumor Microenvironment
D016207:Cytokines; D053583:Interleukin-1beta; D011518:Proto-Oncogene Proteins; C495342:TLR2 protein, human; C495368:TLR6 protein, human; D051195:Toll-Like Receptor 2; D051216:Toll-Like Receptor 6; D020930:MAP Kinase Kinase Kinases; C069937:MAP3K8 protein, human