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Programmed cell death-ligand 1 (PD-L1)+ tumour cells and low-reacting programmed cell death 1 (PD1)+ tumour-infiltrating lymphocytes predict poor prognosis in Epstein–Barr virus+ diffuse large B-cell lymphoma

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Abstract

Epstein–Barr virus (EBV)+ diffuse large B-cell lymphoma (DLBCL) has specific tumour cell characteristics, and these patients have worse outcomes than EBV-negative DLBCL patients. We compared 38 EBV+ DLBCL patients with 43 methotrexate-associated EBV+ B-cell lymphoproliferative disorders (MTX+/EBV+ BLPDs) and 30 non-germinal centre (GC) subtype DLBCL. Lymphoma cells of the EBV+ DLBCL group were positive for BCL2 in 17 patients (44.7%), CMYC in 23 patients (60.5%), and p53 in 33 patients (86.8%), which was significantly higher than in the MTX+/EBV+ BLPD group (P < 0.05), and were positive for CD30 in 29 patients (76.3%), compared with two in non-GC subtype DLBCL (6.7%) (P < 0.0001). Significantly more EBV+ DLBCL patients (n = 16, 42.1%) had programmed cell death-ligand 1 (PD-L1)+ tumour cells than patients with non-GC subtype DLBCL (n = 5, 16.7%; P = 0.024), and PD-L1+ tumour cells were more common in advanced stages than in early stages (P = 0.048). Twenty-five EBV+ DLBCL patients (69.4%) had few reactive PD1+ tumour-infiltrating lymphocytes (TILs), compared with 12 patients with MTX+/EBV+ BLPDs (37.5%) (P = 0.008). In the EBV+ DLBCL group, CD30, BCL2, CMYC, and p53 expression was not related to patient prognosis. Poor outcomes were associated with PD-L1+ tumour cells (P = 0.001) and low-reacting PD1+ TILs (P = 0.02), while their combination conferred a worse outcome (P < 0.0001). Immune evasion by PD-L1+ tumour cells and exhaustion of PD1+ TILs may occur in EBV+ DLBCL patients, and PD-L1/PD1 interactions may influence tumour progression and poor prognosis.

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Acknowledgements

We are grateful to Tomomi Okabe and Tomoko Fukushige for technical assistance with the immunohistochemistry assays. We also thank H. Nikki March, Ph.D, from Edanz (https://jp.edanz.com/ac), for editing a draft of this manuscript.

Funding

This study was supported in part by a Grant-in-Aid for Scientific Research (No. 17K08732) from the Ministry of Education, Science, and Culture of Japan.

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Authors and Affiliations

  1. Graduate School of Medical Sciences, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 8140180, Japan

    Shoichi Kimura, Ziyao Wang & Morishige Takeshita

  2. Department of Pathology, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 8140180, Japan

    Shoichi Kimura, Ziyao Wang & Morishige Takeshita

  3. Department of Pathology, Matsuyama Red Cross Hospital, 1 Bunkyo-cho, Matsuyama, 7910000, Japan

    Yumi Oshiro

  4. Department of Haematology, Clinical Research Centre, National Hospital Organization Kyushu Medical Centre, 1-8-1 Jigyohama, Chuo-ku, Fukuoka, 8108563, Japan

    Hiromi Iwasaki & Masanori Kadowaki

  5. Department of Otolaryngology, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 8140180, Japan

    Yasuhito Mihashi & Toshifumi Sakata

  6. Department of Pathology, Clinical Research Centre, National Hospital Organization Kyushu Medical Centre, 1-8-1 Jigyohama, Chuo-ku, Fukuoka, 8108563, Japan

    Shigeto Kawauchi

  7. Division of Medical Oncology, Haematology and Infectious Disease, Department of Internal Medicine, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 8140180, Japan

    Yasushi Takamatsu

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  1. Shoichi Kimura
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Contributions

SK, YM, and MT contributed to the experimental design. HI, MK, YM, TS, and YT retrieved and reviewed the clinical data. YO, ZW, SK, and MT contributed to the histological diagnosis and collected patient samples. YM and MT performed the IHC scoring. Statistical analysis was performed by TS. The manuscript was written by SK and MT and approved by all contributing authors.

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Correspondence to Morishige Takeshita.

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Kimura, S., Oshiro, Y., Iwasaki, H. et al. Programmed cell death-ligand 1 (PD-L1)+ tumour cells and low-reacting programmed cell death 1 (PD1)+ tumour-infiltrating lymphocytes predict poor prognosis in Epstein–Barr virus+ diffuse large B-cell lymphoma. Clin Exp Med 22, 411–419 (2022). https://doi.org/10.1007/s10238-021-00754-4

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  • DOI: https://doi.org/10.1007/s10238-021-00754-4

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