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CCL17 and CCL22/CCR4 signaling is a strong candidate for novel targeted therapy against nasal natural killer/T-cell lymphoma

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Abstract

Nasal natural killer/T-cell lymphoma (NNKTL) is associated with Epstein–Barr virus and has a poor prognosis because of local invasion and/or multiple dissemination. Various chemokines play a role in tumor proliferation and invasion, and chemokine receptors including the C-C chemokine receptor 4 (CCR4) are recognized as potential targets for treating hematologic malignancies. The aim of the present study was to determine whether specific chemokines are produced by NNKTL. We compared chemokine expression patterns in culture supernatants of NNKTL cell lines with those of other lymphoma or leukemia cell lines using chemokine protein array and ELISA. Chemokine (C-C motif) ligand (CCL) 17 and CCL22 were highly produced by NNKTL cell lines as compared to the other cell lines. In addition, CCL17 and CCL22 were readily observed in the sera of NNKTL patients. The levels of these chemokines were significantly higher in patients than in healthy controls. Furthermore, we detected the expression of CCR4 (the receptor for CCL17 and CCL22) on the surface of NNKTL cell lines and in tissues of NNKTL patients. Anti-CCR4 monoclonal antibody (mAb) efficiently induced antibody-dependent cellular cytotoxicity mediated by natural killer cells against NNKTL cell lines. Our results suggest that CCL17 and CCL22 may be important factors in the development of NNKTL and open up the possibility of immunotherapy of this lymphoma using anti-CCR4 mAb.

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Abbreviations

ADCC:

Antibody-dependent cellular cytotoxicity

ATLL:

Adult T-cell leukemia/lymphoma

CCL:

Chemokine (C-C motif) ligand

CCR4:

C-C chemokine receptor 4

EBV:

Epstein–Barr virus

FBS:

Fetal bovine serum

IL:

Interleukin

IP-10:

Interferon-gamma-inducible protein-10

LDH:

Lactate dehydrogenase

LMP-1:

Latent membrane protein-1

mAbs:

Monoclonal antibodies

MDC:

Macrophage-derived chemokine

miR:

Micro-RNA

NK cell:

Natural killer cell

NNKTL:

Nasal natural killer/T-cell lymphoma

PBMCs:

Peripheral blood mononuclear cells

PBS:

Phosphate-buffered saline

TARC:

Thymus and activation-regulated chemokine

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Acknowledgments

The authors thank Dr. Shimizu N (Tokyo Medical and Dental University) and Prof. Klein E (Karolinska Institute) for generously providing cell lines. This study was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI [Grant Numbers 24791735 (Kumai T), 23791869 (Nagato T), 25460430 (Kobayashi H), and 24390385 (Harabuchi Y)] and by National Institutes of Health (NIH) Grants [Grant Numbers R01CA136828 and R01CA157303 (Celis E)].

Conflict of interest

The authors have no financial conflict of interest.

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    Authors and Affiliations

    1. Department of Otolaryngology-Head and Neck Surgery, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa, 078-8510, Japan

      Takumi Kumai, Toshihiro Nagato, Yuki Komabayashi, Seigo Ueda, Kan Kishibe, Miki Takahara & Yasuaki Harabuchi

    2. Department of Pathology, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa, 078-8510, Japan

      Takumi Kumai, Hiroya Kobayashi & Takayuki Ohkuri

    3. Cancer Immunology, Inflammation and Tolerance Program, Georgia Regents University Cancer Center, Augusta, GA, USA

      Esteban Celis

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    1. Takumi Kumai
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    Correspondence to Toshihiro Nagato or Hiroya Kobayashi.

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    Takumi Kumai and Toshihiro Nagato contributed equally to this work.

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    Kumai, T., Nagato, T., Kobayashi, H. et al. CCL17 and CCL22/CCR4 signaling is a strong candidate for novel targeted therapy against nasal natural killer/T-cell lymphoma. Cancer Immunol Immunother 64, 697–705 (2015). https://doi.org/10.1007/s00262-015-1675-7

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