title: Programmed death-ligand 1 and its soluble form are highly expressed in nasal natural killer/T-cell lymphoma: a potential rationale for immunotherapy.
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.
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa, 078-8510, Japan. rijun@asahikawa-med.ac.jp.|Department of Pathology, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa, 078-8510, Japan. rijun@asahikawa-med.ac.jp.
authors.forename: Toshihiro
authors.identifier: http://orcid.org/0000-0001-8326-8296
authors.initials: T
authors.lastname: Nagato
authors.affiliation: Department of Pathology, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa, 078-8510, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Ohkuri
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa, 078-8510, Japan.|Department of Pathology, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa, 078-8510, Japan.
authors.forename: Kenzo
authors.initials: K
authors.lastname: Ohara
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa, 078-8510, Japan.|Department of Pathology, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa, 078-8510, Japan.
authors.forename: Yui
authors.initials: Y
authors.lastname: Hirata
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa, 078-8510, Japan.
authors.forename: Kan
authors.initials: K
authors.lastname: Kishibe
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa, 078-8510, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Komabayashi
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa, 078-8510, Japan.
authors.forename: Seigo
authors.initials: S
authors.lastname: Ueda
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa, 078-8510, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Takahara
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa, 078-8510, Japan.|Department of Pathology, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa, 078-8510, Japan.
authors.forename: Takumi
authors.initials: T
authors.lastname: Kumai
authors.affiliation: Department of Pathology, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa, 078-8510, Japan.|Respiratory and Breast Center, Asahikawa Medical University Hospital, Asahikawa, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Ishibashi
authors.affiliation: Department of Pathology, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa, 078-8510, Japan.
authors.forename: Akemi
authors.initials: A
authors.lastname: Kosaka
authors.affiliation: Department of Pathology, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa, 078-8510, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Aoki
authors.affiliation: Department of Pathology, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa, 078-8510, Japan.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Oikawa
authors.affiliation: Department of Surgical Pathology, Asahikawa Medical University Hospital, Asahikawa, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Uno
authors.affiliation: Department of Surgical Pathology, Asahikawa Medical University Hospital, Asahikawa, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Akiyama
authors.affiliation: Department of Surgical Pathology, Asahikawa Medical University Hospital, Asahikawa, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Sado
authors.affiliation: Department of Surgical Pathology, Asahikawa Medical University Hospital, Asahikawa, Japan.
authors.forename: Hidehiro
authors.initials: H
authors.lastname: Takei
authors.affiliation: Cancer Immunology, Inflammation and Tolerance Program, Georgia Cancer Center, Augusta University, Augusta, GA, USA.
authors.forename: Esteban
authors.initials: E
authors.lastname: Celis
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa, 078-8510, Japan.
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Harabuchi
authors.affiliation: Department of Pathology, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa, 078-8510, Japan. hiroya@asahikawa-med.ac.jp.
authors.forename: Hiroya
authors.initials: H
authors.lastname: Kobayashi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D001706:Biopsy; D045744:Cell Line, Tumor; D018572:Disease-Free Survival; D005260:Female; D064593:Heterografts; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D053208:Kaplan-Meier Estimate; D054391:Lymphoma, Extranodal NK-T-Cell / Q000378:metabolism / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D008297:Male; D051379:Mice; D008875:Middle Aged; D009669:Nose Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D011379:Prognosis; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism*
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor
keywords: Immunotherapy; Nasal NK/T-cell lymphoma; PD-1; PD-L1; Soluble form