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- Title
Interleukin-38 promotes tumor growth through regulation of CD8+ tumor-infiltrating lymphocytes in lung cancer tumor microenvironment.
- Authors
Kinoshita, Fumihiko; Tagawa, Tetsuzo; Akamine, Takaki; Takada, Kazuki; Yamada, Yuichi; Oku, Yuka; Kosai, Keisuke; Ono, Yuki; Tanaka, Kensuke; Wakasu, Sho; Oba, Taro; Osoegawa, Atsushi; Shimokawa, Mototsugu; Oda, Yoshinao; Hoshino, Tomoaki; Mori, Masaki
- 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.
- Subjects
TUMOR growth; TUMOR microenvironment; LUNG cancer; LUNG tumors; LYMPHOCYTES
- Publication
Cancer Immunology, Immunotherapy, 2021, Vol 70, Issue 1, p123
- ISSN
0340-7004
- Publication type
Article
- DOI
10.1007/s00262-020-02659-9