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

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.