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Programmed death-ligand 1 and its soluble form are highly expressed in nasal natural killer/T-cell lymphoma: a potential rationale for immunotherapy

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Abstract

Nasal natural killer/T-cell lymphoma (NNKTL) is an aggressive neoplasm with poor therapeutic responses and prognosis. The programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) pathway plays an important role in immune evasion of tumor cells through T-cell exhaustion. The aim of the present study was to examine the expression of PD-L1 and PD-1 molecules in NNKTL. We detected the expression of PD-L1 in biopsy samples from all of the NNKTL patients studied. PD-L1 was found on both malignant cells and tumor-infiltrating macrophages, while PD-1-positive mononuclear cells infiltrated the tumor tissues in 36% of patients. Most significantly, soluble PD-L1 (sPD-L1) was present in sera of NNKTL patients at higher levels as compared to healthy individuals and the levels of serum sPD-L1 in patients positively correlated with the expression of PD-L1 in lymphoma cells of tumor tissues. In addition, the high-sPD-L1 group of patients showed significantly worse prognosis than the low-sPD-L1 group. Furthermore, we confirmed that membrane and soluble PD-L1 was expressed on the surface and in the culture supernatant, respectively, of NNKTL cell lines. The expression of PD-L1 was observed in tumor tissues and sera from a murine xenograft model inoculated with an NNKTL cell line. Our results suggest that sPD-L1 could be a prognostic predictor for NNKTL and open up the possibility of immunotherapy of this lymphoma using PD-1/PD-L1 axis inhibitors.

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Abbreviations

CAEBV:

Chronic active Epstein–Barr virus infection

CTLs:

Cytotoxic T lymphocytes

EBER:

Epstein–Barr virus encoded small RNA

EBV:

Epstein–Barr virus

FBS:

Fetal bovine serum

FFPE:

Formalin-fixed, paraffin-embedded

IFN:

Interferon

IL:

Interleukin

IPI:

International Prognostic Index

ISH:

In situ hybridization

LDH:

Lactate dehydrogenase

LMP:

Latent membrane protein

mAbs:

Monoclonal antibodies

NK:

Natural killer

NNKTL:

Nasal natural killer/T-cell lymphoma

OS:

Overall survival

PD-1:

Programmed death-1

PD-L1:

Programmed death-ligand 1

PINK:

Prognostic index of natural killer lymphoma

ROC:

Receiver-operating characteristic

RT:

Room temperature

sPD-L1:

Soluble programmed death-ligand 1

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Acknowledgements

The authors thank Dr. Norio Shimizu (Tokyo Medical and Dental University) for generously providing cell lines, Mr. Toshiyuki Hayakawa (Animal Laboratory for Medical Research, Center for Advanced Research and Education, Asahikawa Medical University) for devotedly maintaining mice, and Ms. Rie Matsumoto (Department of Pathology, Asahikawa Medical University) and Ms. Keiko Nishikura (Department of Dermatology, Asahikawa Medical University) for technical assistance. This study was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI [Grant Numbers 15K20172 (Nagato T), 26462576 (Kishibe K), 15H04986 (Harabuchi Y), and 16K15244 (Kobayashi H)].

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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

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

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

    Toshihiro Nagato, Takayuki Ohkuri, Kenzo Ohara, Yui Hirata, Takumi Kumai, Kei Ishibashi, Akemi Kosaka, Naoko Aoki, Kensuke Oikawa & Hiroya Kobayashi

  3. Respiratory and Breast Center, Asahikawa Medical University Hospital, Asahikawa, Japan

    Kei Ishibashi

  4. Department of Surgical Pathology, Asahikawa Medical University Hospital, Asahikawa, Japan

    Yuji Uno, Naoko Akiyama, Masatoshi Sado & Hidehiro Takei

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

    Esteban Celis

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  1. Toshihiro Nagato
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Nagato, T., Ohkuri, T., Ohara, K. et al. Programmed death-ligand 1 and its soluble form are highly expressed in nasal natural killer/T-cell lymphoma: a potential rationale for immunotherapy. Cancer Immunol Immunother 66, 877–890 (2017). https://doi.org/10.1007/s00262-017-1987-x

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