Toll-like receptor-4 signaling in mantle cell lymphoma

Effects on tumor growth and immune evasion

Authors

  • Lijuan Wang MD,

    1. Department of Lymphoma/Myeloma, Center for Cancer Immunology Research, Division of Cancer Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
    2. Bone Marrow Transplantation Center, Department of Hematology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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  • Yi Zhao MD,

    1. Bone Marrow Transplantation Center, Department of Hematology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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  • Jianfei Qian PhD,

    1. Department of Lymphoma/Myeloma, Center for Cancer Immunology Research, Division of Cancer Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
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  • Luhong Sun MD, PhD,

    1. Department of Lymphoma/Myeloma, Center for Cancer Immunology Research, Division of Cancer Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
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  • Yong Lu PhD,

    1. Department of Lymphoma/Myeloma, Center for Cancer Immunology Research, Division of Cancer Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
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  • Haiyan Li MD, PhD,

    1. Department of Lymphoma/Myeloma, Center for Cancer Immunology Research, Division of Cancer Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
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  • Yi Li MD,

    1. Bone Marrow Transplantation Center, Department of Hematology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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  • Jing Yang MD, PhD,

    1. Department of Lymphoma/Myeloma, Center for Cancer Immunology Research, Division of Cancer Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
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  • Zhen Cai MD, PhD,

    Corresponding author
    1. Bone Marrow Transplantation Center, Department of Hematology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
    • Zhen Cai, Bone Marrow Transplantation Center, Department of Hematology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China

      Qing Yi, Department of Lymphoma/Myeloma, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 0903, Houston, TX 77030

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    • Fax: (011) 86-571-87236703

  • Qing Yi MD, PhD

    Corresponding author
    1. Department of Lymphoma/Myeloma, Center for Cancer Immunology Research, Division of Cancer Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
    • Zhen Cai, Bone Marrow Transplantation Center, Department of Hematology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China

      Qing Yi, Department of Lymphoma/Myeloma, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 0903, Houston, TX 77030

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    • Fax: (713) 563-9241


  • The first 3 authors and the last 2 authors contributed equally to this article. The first 3 authors and the last 2 authors initiated the work, designed the experiments, and wrote the article; the first 7 authors performed the experiments and statistical analyses; and the eighth author provided critical suggestions for this article.

Abstract

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. Cancer 2013. © 2012 American Cancer Society.

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