Toll-like receptor-4 signaling in mantle cell lymphoma: effects on tumor growth and immune evasion.
BACKGROUND
Mantle cell lymphoma (MCL) is an incurable B-cell malignancy, and patients with this disease have the poorest prognosis among all patients with B-cell lymphomas. The signaling pathways that trigger MCL escape from immune surveillance are unclear. Because Toll-like receptors (TLRs) initiate innate and adaptive immune responses against invading pathogens, the authors investigated the impact of TLR signaling in MCL cells.


METHODS
TLR expression was examined in MCL cell lines and in primary tumors. The examination focused on TLR4 and its ligand lipopolysaccharide (LPS) on MCL cells and their function on MCL proliferation and immune evasion.


RESULTS
MCL cells expressed multiple TLRs, and TLR4 was among the highest expressed molecules. The activation of TLR4 signaling in MCL cells by LPS induced MCL proliferation and up-regulated the secretion of cytokines like interleukin-6 (IL-6), IL-10, and vascular endothelial growth factor (VEGF). LPS-pretreated MCL cells inhibited the proliferation and cytolytic activity of T cells by secreted IL-10 and VEGF, and neutralizing antibodies against these cytokines restored their functions. Similar results were observed in TLR4-positive/myeloid differentiation 88 (MyD88)-positive primary lymphoma cells but not in TLR4-positive/MyD88-negative primary lymphoma cells from patients with MCL. Knockdown of TLR4 on MCL cells abrogated the effect of LPS on MCL cells in term of cell growth or secretion of the cytokines and evasion of the immune system.


CONCLUSIONS
The current results indicated that TLR4 signaling triggers a cascade that leads to MCL growth and evasion from immune surveillance. Thus, TLR4 signaling molecules may be novel therapeutic targets in patients with MCL.
Department of Lymphoma/Myeloma, Center for Cancer Immunology Research, Division of Cancer Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA.
Lijuan
L
Wang
Yi
Y
Zhao
Jianfei
J
Qian
Luhong
L
Sun
Yong
Y
Lu
Haiyan
H
Li
Yi
Y
Li
Jing
J
Yang
Zhen
Z
Cai
Qing
Q
Yi
D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation; D006801:Humans; D057131:Immune Evasion; D016753:Interleukin-10 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D020522:Lymphoma, Mantle-Cell / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000276:immunology / Q000378:metabolism*; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D015850:Interleukin-6; D008070:Lipopolysaccharides; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D016753:Interleukin-10; D019869:Phosphatidylinositol 3-Kinases