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Expression of soluble CD27 in extranodal natural killer/T-cell lymphoma, nasal type: potential as a biomarker for diagnosis and CD27/CD70-targeted therapy

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Abstract

The engagement of CD27 on lymphocytes with its ligand, CD70, on tumors is believed to mediate tumor immune evasion and the elevation of serum soluble CD27 (sCD27) levels in patients with CD70-positive malignancies. We previously showed that CD70 is expressed in extranodal natural killer/T-cell lymphoma, nasal type (ENKL), an Epstein–Barr virus (EBV)-related malignancy. However, little is known about serum sCD27 expression and its association with the clinical characteristics of, and the CD27/CD70 interaction in, ENKL. In the present study, we show that serum sCD27 is significantly elevated in the sera of patients with ENKL. The levels of serum sCD27 provided excellent diagnostic accuracy for discriminating patients with ENKL from healthy subjects, correlated positively with the levels of other diagnostic markers (lactate dehydrogenase, soluble interleukin-2 receptor, and EBV-DNA), and decreased significantly following treatment. Elevated serum sCD27 levels also correlated significantly with advanced clinical stage and tended to correspond with shorter survival, in patients with ENKL. Immunohistochemistry indicated that CD27-positive tumor-infiltrating immune cells exist adjacent to CD70-positive lymphoma cells. In addition, serum sCD27 levels in patients with CD70-positive ENKL were significantly higher than those in patients with CD70-negative ENKL, suggesting that the intra-tumoral CD27/CD70 interaction boosts the release of sCD27 in serum. Furthermore, the EBV-encoded oncoprotein latent membrane protein 1 upregulated CD70 expression in ENKL cells. Our results suggest that sCD27 may serve as a novel diagnostic biomarker and also may serve as a tool for evaluating the applicability of CD27/CD70-targeted therapies by predicting intra-tumoral CD70 expression and CD27/CD70 interaction in ENKL.

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Data availability

The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

Ab:

Antibody

AUC:

Area under the curve

CCL:

Chemokine (C–C motif) ligand

CD40L:

CD40 ligand

EBER:

Epstein–Barr virus-encoded small RNA

EBV:

Epstein–Barr virus

ECOG PS:

Eastern Cooperative Oncology Group Performance Status

ENKL:

Extranodal natural killer/T-cell lymphoma, nasal type

FFPE:

Formalin-fixed, paraffin-embedded

IL:

Interleukin

IPI:

International Prognostic Index

LDH:

Lactate dehydrogenase

LMP1:

Latent membrane protein 1

NK:

Natural killer

PINK:

Prognostic index of natural killer lymphoma

RCC:

Renal cell carcinoma

ROC:

Receiver operating characteristic

sCD27:

Soluble CD27

sIL-2R:

Soluble IL-2 receptor

sPD-L1:

Soluble programmed death-ligand 1

TIL:

Tumor-infiltrating lymphocyte

TNF:

Tumor necrosis factor

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Acknowledgements

The authors thank Dr. Norio Shimizu (Tokyo Medical and Dental University) for generously providing the cell line, and Ms. Rie Matsumoto (Department of Pathology, Asahikawa Medical University) and Ms. Keiko Nishikura (Department of Dermatology, Asahikawa Medical University) for technical assistance.

Funding

This work was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI [Grant No. 18K09310 (Nagato T), 21K09599 (Nagato T), 21H03082 (Harabuchi Y), and 22H02838 (Kobayashi H)].

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Authors and Affiliations

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

    Toshihiro Nagato, Hiroki Komatsuda, Shunsuke Yasuda, Yuki Yajima, Akemi Kosaka, Takayuki Ohkuri, Kensuke Oikawa & Hiroya Kobayashi

  2. Department of Otolaryngology-Head and Neck Surgery, Asahikawa Medical University, Asahikawa, Japan

    Hiroki Komatsuda, Ryusuke Hayashi, Miki Takahara, Kan Kishibe, Shohei Harabuchi, Michihisa Kono, Hidekiyo Yamaki, Risa Wakisaka, Yui Hirata-Nozaki, Kenzo Ohara, Takumi Kumai, Akihiro Katada, Tatsuya Hayashi & Yasuaki Harabuchi

  3. Department of Innovative Research for Diagnosis and Treatment of Head and Neck Cancer, Asahikawa Medical University, Asahikawa, Japan

    Miki Takahara & Takumi Kumai

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

    Shunsuke Yasuda

  5. Department of Oral and Maxillofacial Surgery, Asahikawa Medical University, Asahikawa, Japan

    Yuki Yajima

  6. Department of Otolaryngology-Head and Neck Surgery, Hokuto Hospital, Obihiro, Japan

    Yasuaki Harabuchi

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  1. Toshihiro Nagato
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Contributions

TN and HK conceptualized and designed the study. TN, HK, RH, MT, KK, SH, MK, HY, RW, YH-N, KO, TK, AK, TH, and YH performed patient management and material preparation. TN performed experiments. TN, HK, RH, and HK analyzed and interpreted data. TN, HK, RH, SY, YY, AK, TO, KO, and HK discussed the results. TN wrote the first draft of the manuscript, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Toshihiro Nagato or Hiroya Kobayashi.

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This study was performed in compliance with the principles of the Declaration of Helsinki and subsequent amendments, and the study protocol was approved by the Institutional Review Board of the Asahikawa Medical University (#1332–3).

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Nagato, T., Komatsuda, H., Hayashi, R. et al. Expression of soluble CD27 in extranodal natural killer/T-cell lymphoma, nasal type: potential as a biomarker for diagnosis and CD27/CD70-targeted therapy. Cancer Immunol Immunother 72, 2087–2098 (2023). https://doi.org/10.1007/s00262-023-03394-7

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