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Interleukin-38 promotes tumor growth through regulation of CD8+ tumor-infiltrating lymphocytes in lung cancer tumor microenvironment

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Abstract

Background

Interleukin (IL)-38 was discovered in 2001 and is a member of the IL-1 family of cytokines. IL-38 shows anti-inflammatory activity in several inflammatory diseases. In lung adenocarcinoma, we previously demonstrated that high IL-38 expression in tumor cells was associated with poor prognosis. However, the role of IL-38 in the tumor microenvironment has not been clarified.

Methods

IL-38-plasmid-transfected Lewis lung carcinoma cells (LLC-IL38) and empty vector-transfected LLC cells (LLC-vector) were established. Cell proliferation in vitro and tumor growth in vivo were examined, and immunohistochemical staining was used to assess tumor-infiltrating lymphocytes (TILs). A CD8+ lymphocyte depletion model was established to show the association between IL-38 and CD8+ lymphocytes. Moreover, we examined the association between IL-38 expression and CD8+ TILs in human samples, analyzing immunohistochemical staining in 226 patients with radically resected lung adenocarcinoma.

Results

Tumor growth of LLC-IL38 in vivo was significantly increased compared with that of LLC-vector, although cell proliferation of LLC-IL38 in vitro was lower than that of LLC-vector. CD8+ TILs were significantly decreased in LLC-IL38 tumor compared with LLC-vector tumor. The difference in tumor growth between LLC-IL38 and LLC-vector became insignificant after depletion of CD8+ lymphocytes. In immunohistochemical staining in tissues from patients with lung adenocarcinoma, multivariate analysis showed high IL-38 expression was an independent negative predicter of high density of CD8+ TILs.

Conclusion

We demonstrated that high IL-38 expression in tumor cells was significantly associated with reduction of CD8+ TILs and tumor progression. These results suggest that IL-38 could be a therapeutic target for lung cancer.

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Data availability

The data used to support the findings of our study are available from the corresponding author upon reasonable request.

Abbreviations

LLC-vector:

Empty-vector-transfected LLC cells

IL:

Interleukin

IFN-γ:

Interferon-γ

IL-36R:

IL-36 receptor

LLC-IL38:

IL-38-plasmid-transfected LLC cells

LLC:

Lewis lung carcinoma

MDSCs:

Myeloid-derived suppressor cells

NK:

Natural killer

NSCLC:

Non-small cell lung cancer

PD-1:

Programmed cell death-1

PD-L1:

Programmed cell death-ligand 1

RT:

Reversed transcription

Tregs:

Regulatory T cells

TILs:

Tumor-infiltrating lymphocytes

TNF-α:

Tumor necrosis factor-α

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Acknowledgements

We thank Saori Tsurumaru, Emi Kamiya, Asuka Nakamura, Miki Nakashima, Yuko Kubota and Natsumi Maeda (Junior Laboratory Animal Technician) for their invaluable help with in vitro examination, tissue processing and animal experiments. We also thank Cathel Kerr, BSc, PhD, from Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript.

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Authors and Affiliations

  1. Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan

    Fumihiko Kinoshita, Tetsuzo Tagawa, Takaki Akamine, Kazuki Takada, Yuka Oku, Keisuke Kosai, Yuki Ono, Kensuke Tanaka, Sho Wakasu, Taro Oba, Atsushi Osoegawa & Masaki Mori

  2. Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Yuichi Yamada & Yoshinao Oda

  3. Department of Biostatistics, Graduate School of Medicine, Yamaguchi University, Yamaguchi, Japan

    Mototsugu Shimokawa

  4. Department of Medicine, Division of Respirology, Neurology and Rheumatology, Kurume University School of Medicine, Fukuoka, Japan

    Tomoaki Hoshino

Authors
  1. Fumihiko Kinoshita
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  2. Tetsuzo Tagawa
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Contributions

Conception and design: FK, KT, TT, MM. Development of methodology: FK, TA, KT, TT. Acquisition of data: FK, TA, YY, YO, KK, YO, KT, SW. Analysis and interpretation of data: FK, TA, KT, TO, AO, TT, MS, YO, TH, MM. Writing, review, and/or revision of manuscript: FK, TT, TH, MM. Study supervision: TT, MS, YO, TH, MM.

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Correspondence to Tetsuzo Tagawa.

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Kinoshita, F., Tagawa, T., Akamine, T. et al. Interleukin-38 promotes tumor growth through regulation of CD8+ tumor-infiltrating lymphocytes in lung cancer tumor microenvironment. Cancer Immunol Immunother 70, 123–135 (2021). https://doi.org/10.1007/s00262-020-02659-9

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  • DOI: https://doi.org/10.1007/s00262-020-02659-9

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