Interleukin‐33 as an early predictor of cetuximab treatment efficacy in patients with colorectal cancer

BACKGROUND: Cetuximab is used for colorectal cancer (CRC) treatment. However, the early biomarker of treatment efficacy of cetuximab has not been identified. METHODS: After 1 year of cetuximab treatment, patients were divided into an effective group and an ineffective group. The interleukin‐33 (IL‐33) level and the distribution of lymphatic cells in patients were investigated by analyzing the peripheral blood mononuclear cells via flow cytometry analysis and ELISA. The correlation between IL‐33 immunomodulatory effect and cetuximab treatment efficacy was determined through experiments in vivo and in vitro. RESULTS: The IL‐33 level in the peripheral blood was increased at 4 weeks after cetuximab administration of effective group, meanwhile, the osteopontin (OPN) was reduced. Whereas neither IL‐33 level nor OPN level of ineffective patients changed. In the effective group, the number of natural killer (NK) and CD8(+) T cells were increased. Moreover, CD137 and CD107a expression on NK cells were higher in the effective group compared to the ineffective group. In vitro cetuximab treatment also increased the number of NK and CD8(+) T cells as well as CD137 and CD107a expression upon IL‐33 stimulation. Moreover, the secretion of OPN was inhibited by IL‐33 administration in cetuximab‐treated PBMCs from the effective group patients. IL‐33 upregulated the cytotoxicity of NK cells and inhibited tumor cells growth in the effective cetuximab treatment mice. CONCLUSION: Effective cetuximab treatment induced a change of IL‐33 and OPN at the early stage and triggered the NK cells antitumor activity. Consequently, significantly increased IL‐33 level and decreased OPN level in the peripheral blood at the early treatment are proposed as potential predictors of cetuximab treatment efficacy.