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11.07.2020 | Original Article

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

verfasst von: Fumihiko Kinoshita, Tetsuzo Tagawa, Takaki Akamine, Kazuki Takada, Yuichi Yamada, Yuka Oku, Keisuke Kosai, Yuki Ono, Kensuke Tanaka, Sho Wakasu, Taro Oba, Atsushi Osoegawa, Mototsugu Shimokawa, Yoshinao Oda, Tomoaki Hoshino, Masaki Mori

Erschienen in: Cancer Immunology, Immunotherapy | Ausgabe 1/2021

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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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Titel: Interleukin-38 promotes tumor growth through regulation of CD8+ tumor-infiltrating lymphocytes in lung cancer tumor microenvironment
verfasst von: Fumihiko Kinoshita
Tetsuzo Tagawa
Takaki Akamine
Kazuki Takada
Yuichi Yamada
Yuka Oku
Keisuke Kosai
Yuki Ono
Kensuke Tanaka
Sho Wakasu
Taro Oba
Atsushi Osoegawa
Mototsugu Shimokawa
Yoshinao Oda
Tomoaki Hoshino
Masaki Mori
Publikationsdatum: 11.07.2020
Verlag: Springer Berlin Heidelberg
Erschienen in: Cancer Immunology, Immunotherapy / Ausgabe 1/2021
Print ISSN: 0340-7004
Elektronische ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-020-02659-9

Springer Medizin

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